БИОХИМИЯ, 2020, том 85, вып. 9, с. 1159–1188

УДК 577.053, 616-006.04, 615.277.3

Рецептор эпидермального фактора роста: ключ для селективной доставки в клетки*

Обзор

© 2020 А.А. Розенкранц 1,2**, Т.А. Сластникова 2

Московский государственный университет имени М.В. Ломоносова, биологический факультет, 119234 Москва, Россия; электронная почта: aar@igb.ac.ru

Институт биологии гена РАН, 119334 Москва, Россия

Поступила в редакцию 15.06.2020
После доработки 23.07.2020
Принята к публикации 23.07.2020

DOI: 10.31857/S032097252009002X

КЛЮЧЕВЫЕ СЛОВА: рецептор эпидермального фактора роста, сверхэкспрессия, рак, эндоцитоз, направленная терапия рака, доставка лекарств.

Аннотация

Рецептор эпидермального фактора роста (epidermal growth factor receptor, EGFR) – интегральный поверхностный белок, который обусловливает ответ клеток на ряд факторов роста. Увеличение его экспрессии и активности за счет мутаций являются одними из наиболее часто встречающихся признаков клеток многих видов рака. Разработка и клиническое применение средств блокирования активации EGFR стали ярким примером использования персонализованной таргетной медицины. Несмотря на очевидные успехи этого направления, в большинстве случаев излечение рака остается недостижимым. Причины этого, а также поиск возможных путей преодоления сложностей лечения привели к появлению огромного количества разработок новых методов лечения, опирающихся на использование сверхэкспрессии EGFR и его изменений для уничтожения раковых клеток. В обзоре рассмотрены и структурированы современные данные о строении, функционировании и внутриклеточном транспорте EGFR, его природных лигандах, а также запускаемых при активации EGFR сигнальных каскадах, особенностях экспрессии и активации EGFR при онкологических заболеваниях, а также о применяемых терапевтических подходах, направленных на блокировку сигнального пути EGFR. Подробно рассмотрены создаваемые подходы к адресной доставке внутрь раковых клеток с увеличенной экспрессией EGFR различных химиотерапевтических средств, радионуклидов, иммунотоксинов, фотосенсибилизаторов, а также перспективы генной терапии таких клеток-мишеней. Необходимо отметить, что все большее внимание уделяется разработке многофункциональных систем, как несущих несколько разных действующих агентов, так и обладающих несколькими зависящими от окружения транспортными функциями. Обсуждается потенциал систем, основанных на рецептор-опосредуемом эндоцитозе EGFR, их возможные достоинства и ограничения.

Сноски

* Статья на английском языке опубликована в режиме Open Access (открытого доступа) на сайте издательства Springer (https://link.springer.com/journal/10541), том 85, вып. 9, 2020.

** Адресат для корреспонденции.

Финансирование

Работа была выполнена при поддержке Российского фонда фундаментальных исследований (грант № 19-14-50385 19).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит каких-либо исследований с участием людей или использованием животных в качестве объектов.

Список литературы

1. Jorissen, R. N., Walker, F., Pouliot, N., Garrett, T. P., Ward, C. W., and Burgess, A. W. (2003) Epidermal growth factor receptor: mechanisms of activation and signalling, Exp. Cell Res., 284, 31-53, doi: 10.1016/s0014-4827(02)00098-8.

2. Yarden, Y., and Pines, G. (2012) The ERBB network: at last, cancer therapy meets systems biology, Nat. Rev. Cancer, 12, 553-563, doi: 10.1038/nrc3309.

3. Roskoski, R., Jr. (2014) The ErbB/HER family of protein-tyrosine kinases and cancer, Pharmacol. Res., 79, 34-74, doi: 10.1016/j.phrs.2013.11.002.

4. Lamouille, S., Xu, J., and Derynck, R. (2014) Molecular mechanisms of epithelial-mesenchymal transition, Nat. Rev. Mol. Cell Biol., 15, 178-196, doi: 10.1038/nrm3758.

5. Sigismund, S., Avanzato, D., and Lanzetti, L. (2018) Emerging functions of the EGFR in cancer, Mol. Oncol., 12, 3-20, doi: 10.1002/1878-0261.12155.

6. Lemmon, M. A., Schlessinger, J., and Ferguson, K. M. (2014) The EGFR family: not so prototypical receptor tyrosine kinases, Cold Spring Harb. Perspect. Biol., 6, a020768, doi: 10.1101/cshperspect.a020768.

7. Arkhipov, A., Shan, Y., Das, R., Endres, N. F.,Eastwood, M. P., Wemmer, D. E., Kuriyan, J., and Shaw, D. E. (2013) Architecture and membrane interactions of the EGF receptor, Cell, 152, 557-569, doi: 10.1016/j.cell.2012.12.030.

8. Purba, E. R., Saita, E. I., and Maruyama, I. N. (2017) Activation of the EGF receptor by ligand binding and oncogenic mutations: the “rotation model”, Cells, 6, 13, doi: 10.3390/cells6020013.

9. Holbro, T., and Hynes, N. E. (2004) ErbB receptors: directing key signaling networks throughout life, Annu. Rev. Pharmacol. Toxicol., 44, 195-217, doi: 10.1146/annurev.pharmtox.44.101802.121440.

10. Frolov, A., Schuller, K., Tzeng, C. W., Cannon, E. E., Ku, B. C., Howard, J. H., Vickers, S. M., Heslin, M. J., Buchsbaum, D. J., and Arnoletti, J. P. (2007) ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib, Cancer Biol. Ther., 6, 548-554, doi: 10.4161/cbt.6.4.3849.

11. Zhu, S., Belkhiri, A., and El-Rifai, W. (2011) DARPP-32 increases interactions between epidermal growth factor receptor and ERBB3 to promote tumor resistance to gefitinib, Gastroenterology, 141, 1738-1748, doi: 10.1053/j.gastro.2011.06.070.

12. Huang, Z., Wang, Y., Nayak, P. S., Dammann, C. E., and Sanchez-Esteban, J. (2012) Stretch-induced fetal type II cell differentiation is mediated via ErbB1-ErbB4 interactions, J. Biol. Chem., 287, 18091-18102, doi: 10.1074/jbc.M111.313163.

13. Saito, Y., Haendeler, J., Hojo, Y., Yamamoto, K., and Berk, B. C. (2001) Receptor heterodimerization: essential mechanism for platelet-derived growth factor-induced epidermal growth factor receptor transactivation, Mol. Cell. Biol., 21, 6387-6394, doi: 10.1128/mcb.21.19.6387-6394.2001.

14. Black, P. C., Brown, G. A., Dinney, C. P., Kassouf, W., Inamoto, T., Arora, A., Gallagher, D., Munsell, M. F., Bar-Eli, M., McConkey, D. J., and Adam, L. (2011) Receptor heterodimerization: a new mechanism for platelet-derived growth factor induced resistance to anti-epidermal growth factor receptor therapy for bladder cancer, J. Urol., 185, 693-700, doi: 10.1016/j.juro.2010.09.082.

15. Tanizaki, J., Okamoto, I., Sakai, K., and Nakagawa, K. (2011) Differential roles of trans-phosphorylated EGFR, HER2, HER3, and RET as heterodimerisation partners of MET in lung cancer with MET amplification, Br. J. Cancer, 105, 807-813, doi: 10.1038/bjc.2011.322.

16. Peace, B. E., Hill, K. J., Degen, S. J., and Waltz, S. E. (2003) Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor, Exp. Cell Res., 289, 317-325, doi: 10.1016/s0014-4827(03)00280-5.

17. Morgillo, F., Woo, J. K., Kim, E. S., Hong, W. K., and Lee, H. Y. (2006) Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib, Cancer Res., 66, 10100-10111, doi: 10.1158/0008-5472.CAN-06-1684.

18. Needham, S. R., Roberts, S. K., Arkhipov, A., Mysore, V. P., Tynan, C. J., Zanetti-Domingues, L. C., Kim, E. T., Losasso, V., Korovesis, D., Hirsch, M., Rolfe, D. J., Clarke, D. T., Winn, M. D., Lajevardipour, A., Clayton, A. H., Pike, L. J., Perani, M., Parker, P. J., Shan, Y., Shaw, D. E., and Martin-Fernandez, M. L. (2016) EGFR oligomerization organizes kinase-active dimers into competent signalling platforms, Nat. Commun., 7, 13307, doi: 10.1038/ncomms13307.

19. Ibach, J., Radon, Y., Gelleri, M., Sonntag, M. H., Brunsveld, L., Bastiaens, P. I., and Verveer, P. J. (2015) Single particle tracking reveals that EGFR signaling activity is amplified in clathrin-coated pits, PLoS One, 10, e0143162, doi: 10.1371/journal.pone.0143162.

20. Clarke, D. T., and Martin-Fernandez, M. L. (2019) A brief history of single-particle tracking of the epidermal growth factor receptor, Methods Protoc., 2, 12, doi: 10.3390/mps2010012.

21. Lemmon, M. A., and Schlessinger, J. (2010) Cell signaling by receptor tyrosine kinases, Cell, 141, 1117-1134, doi: 10.1016/j.cell.2010.06.011.

22. Macdonald, J. L., and Pike, L. J. (2008) Heterogeneity in EGF-binding affinities arises from negative cooperativity in an aggregating system, Proc. Natl. Acad. Sci. USA, 105, 112-117, doi: 10.1073/pnas.0707080105.

23. Riese, D. J., and Stern, D. F. (1998) Specificity within the EGF family/ErbB receptor family signaling network, Bioessays, 20, 41-48, doi: 10.1002/(SICI)1521-1878(199801)20:1<41::AID-BIES7>3.0.CO;2-V.

24. Wang, Y. N., Lee, H. H., Chou, C. K., Yang, W. H., Wei, Y., Chen, C. T., Yao, J., Hsu, J. L., Zhu, C., Ying, H., Ye, Y., Wang, W. J., Lim, S. O., Xia, W., Ko, H. W., Liu, X., Liu, C. G., Wu, X., Wang, H., Li, D., Prakash, L. R., Katz, M. H., Kang, Y., Kim, M., Fleming, J. B., Fogelman, D., Javle, M., Maitra, A., and Hung, M. C. (2018) Angiogenin/ribonuclease 5 is an EGFR ligand and a serum biomarker for erlotinib sensitivity in pancreatic cancer, Cancer Cell, 33, 752-769, doi: 10.1016/j.ccell.2018.02.012.

25. Wang, Y. N., Lee, H. H., and Hung, M. C. (2018) A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases, J. Biomed. Sci., 25, 83, doi: 10.1186/s12929-018-0484-7.

26. Pinkas-Kramarski, R., Shelly, M., Guarino, B. C., Wang, L. M., Lyass, L., Alroy, I., Alimandi, M., Kuo, A., Moyer, J. D., Lavi, S., Eisenstein, M., Ratzkin, B. J., Seger, R., Bacus, S. S., Pierce, J. H., Andrews, G. C., and Yarden, Y. (1998) ErbB tyrosine kinases and the two neuregulin families constitute a ligand-receptor network, Mol. Cell Biol., 18, 6090-6101, doi: 10.1128/mcb.18.10.6090.

27. Gilmore, J. L., Gallo, R. M., and Riese, D. J. (2006) The epidermal growth factor receptor (EGFR)-S442F mutant displays increased affinity for neuregulin-2beta and agonist-independent coupling with downstream signalling events, Biochem. J., 396, 79-88, doi: 10.1042/BJ20051687.

28. Santra, M., Reed, C. C., and Iozzo, R. V. (2002) Decorin binds to a narrow region of the epidermal growth factor (EGF) receptor, partially overlapping but distinct from the EGF-binding epitope, J. Biol. Chem., 277, 35671-35681, doi: 10.1074/jbc.M205317200.

29. Zhu, J. X., Goldoni, S., Bix, G., Owens, R. T., McQuillan, D. J., Reed, C. C., and Iozzo, R. V. (2005) Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis, J. Biol. Chem., 280, 32468-32479, doi: 10.1074/jbc.M503833200.

30. Goldoni, S., Iozzo, R. A., Kay, P., Campbell, S., McQuillan, A., Agnew, C., Zhu, J. X., Keene, D. R., Reed, C. C., and Iozzo, R. V. (2007) A soluble ectodomain of LRIG1 inhibits cancer cell growth by attenuating basal and ligand-dependent EGFR activity, Oncogene, 26, 368-381, doi: 10.1038/sj.onc.1209803.

31. Zheng, Y., Li, X., Qian, X., Wang, Y., Lee, J. H., Xia, Y., Hawke, D. H., Zhang, G., Lyu, J., and Lu, Z. (2015) Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation, Nat. Cell Biol., 17, 1348-1355, doi: 10.1038/ncb3222.

32. Freed, D. M., Bessman, N. J., Kiyatkin, A., Salazar-Cavazos, E., Byrne, P. O., Moore, J. O., Valley, C. C., Ferguson, K. M., Leahy, D. J., Lidke, D. S., and Lemmon, M. A. (2017) EGFR ligands differentially stabilize receptor dimers to specify signaling kinetics, Cell, 171, 683-695, doi: 10.1016/j.cell.2017.09.017.

33. Macdonald-Obermann, J. L., and Pike, L. J. (2014) Different epidermal growth factor (EGF) receptor ligands show distinct kinetics and biased or partial agonism for homodimer and heterodimer formation, J. Biol. Chem., 289, 26178-26188, doi: 10.1074/jbc.M114.586826.

34. Liao, H. W., Hsu, J. M., Xia, W., Wang, H. L., Wang, Y. N., Chang, W. C., Arold, S. T., Chou, C. K., Tsou, P. H., Yamaguchi, H., Fang, Y. F., Lee, H. J., Lee, H. H., Tai, S. K., Yang, M. H., Morelli, M. P., Sen, M., Ladbury, J. E., Chen, C. H., Grandis, J. R., Kopetz, S., and Hung, M. C. (2015) PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response, J. Clin. Invest., 125, 4529-4543, doi: 10.1172/JCI82826.

35. Wang, W. J., Hsu, J. M., Wang, Y. N., Lee, H. H., Yamaguchi, H., Liao, H. W., and Hung, M. C. (2019) An essential role of PRMT1-mediated EGFR methylation in EGFR activation by ribonuclease 5, Am. J. Cancer Res., 9, 180-185.

36. Caldieri, G., Malabarba, M. G., Di Fiore, P. P., and Sigismund, S. (2018) EGFR trafficking in physiology and cancer, Prog. Mol. Subcell. Biol., 57, 235-272, doi: 10.1007/978-3-319-96704-2_9.

37. Sorkin, A., and Goh, L. K. (2008) Endocytosis and intracellular trafficking of ErbBs, Exp. Cell Res., 315, 683-696, doi: 10.1016/j.yexcr.2008.07.029.

38. Goh, L. K., and Sorkin, A. (2013) Endocytosis of receptor tyrosine kinases, Cold Spring Harb. Perspect. Biol., 5, a017459, doi: 10.1101/cshperspect.a017459.

39. Waterman, H., Levkowitz, G., Alroy, I., and Yarden, Y. (1999) The RING finger of c-Cbl mediates desensitization of the epidermal growth factor receptor, J. Biol. Chem., 274, 22151-22154, doi: 10.1074/jbc.274.32.22151.

40. Jiang, X., Huang, F., Marusyk, A., and Sorkin, A. (2003) Grb2 regulates internalization of EGF receptors through clathrin-coated pits, Mol. Biol. Cell, 14, 858-870, doi: 10.1091/mbc.e02-08-0532.

41. Sigismund, S., Algisi, V., Nappo, G., Conte, A., Pascolutti, R., Cuomo, A., Bonaldi, T., Argenzio, E., Verhoef, L. G., Maspero, E., Bianchi, F., Capuani, F., Ciliberto, A., Polo, S., and Di Fiore, P. P. (2013) Threshold-controlled ubiquitination of the EGFR directs receptor fate, EMBO J., 32, 2140-2157, doi: 10.1038/emboj.2013.149.

42. Huang, F., Goh, L. K., and Sorkin, A. (2007) EGF receptor ubiquitination is not necessary for its internalization, Proc. Natl. Acad. Sci USA, 104, 16904-16909.

43. Goh, L. K., Huang, F., Kim, W., Gygi, S., and Sorkin, A. (2010) Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor, J. Cell Biol., 189, 871-883, doi: 10.1083/jcb.201001008.

44. Oved, S., Mosesson, Y., Zwang, Y., Santonico, E., Shtiegman, K., Marmor, M. D., Kochupurakkal, B. S., Katz, M., Lavi, S., Cesareni, G., and Yarden, Y. (2006) Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases, J. Biol. Chem., 281, 21640-21651, doi: 10.1074/jbc.M513034200.

45. Boucrot, E., Ferreira, A. P., Almeida-Souza, L., Debard, S., Vallis, Y., Howard, G., Bertot, L., Sauvonnet, N., and McMahon, H. T. (2015) Endophilin marks and controls a clathrin-independent endocytic pathway, Nature, 517, 460-465, doi: 10.1038/nature14067.

46. Sigismund, S., Argenzio, E., Tosoni, D., Cavallaro, E., Polo, S., and Di Fiore, P. P. (2008) Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation, Dev. Cell, 15, 209-219, doi: 10.1016/j.devcel.2008.06.012.

47. Sorkin, A., Krolenko, S., Kudrjavtceva, N., Lazebnik, J., Teslenko, L., Soderquist, A. M., and Nikolsky, N. (1991) Recycling of epidermal growth factor-receptor complexes in A431 cells: identification of dual pathways, J. Cell Biol., 112, 55-63, doi: 10.1083/jcb.112.1.55.

48. Soubeyran, P., Kowanetz, K., Szymkiewicz, I., Langdon, W. Y., and Dikic, I. (2002) Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors, Nature, 416, 183-187, doi: 10.1038/416183a.

49. Henriksen, L., Grandal, M. V., Knudsen, S. L. J., van Deurs, B., and Grovdal, L. M. (2013) Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands, PLoS One, 8, e58148, doi: 10.1371/journal.pone.0058148.

50. West, M. A., Bretscher, M. S., and Watts, C. (1989) Distinct endocytotic pathways in epidermal growth factor-stimulated human carcinoma A431 cells, J. Cell Biol., 109, 2731-2739, doi: 10.1083/jcb.109.6.2731.

51. Yamazaki, T., Zaal, K., Hailey, D., Presley, J., Lippincott-Schwartz, J., and Samelson, L. E. (2002) Role of Grb2 in EGF-stimulated EGFR internalization, J. Cell Sci., 115, 1791-1802.

52. Orth, J. D., Krueger, E. W., Weller, S. G., and McNiven, M. A. (2006) A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization, Cancer Res., 66, 3603-3610, doi: 10.1158/0008-5472.CAN-05-2916.

53. Tomas, A., Futter, C. E., and Eden, E. R. (2014) EGF receptor trafficking: consequences for signaling and cancer, Trends Cell Biol., 24, 26-34.

54. Wang, Y. N., Wang, H., Yamaguchi, H., Lee, H. J., Lee, H. H., and Hung, M. C. (2010) COPI-mediated retrograde trafficking from the Golgi to the ER regulates EGFR nuclear transport, Biochem. Biophys. Res. Commun., 399, 498-504, doi: 10.1016/j.bbrc.2010.07.096.

55. Demory, M. L., Boerner, J. L., Davidson, R., Faust, W., Miyake, T., Lee, I., Huttemann, M., Douglas, R., Haddad, G., and Parsons, S. J. (2009) Epidermal growth factor receptor translocation to the mitochondria: regulation and effect, J. Biol. Chem., 284, 36592-36604, doi: 10.1074/jbc.M109.000760.

56. Cao, X., Zhu, H., Ali-Osman, F., and Lo, H. W. (2011) EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: a potential mechanism of EGFR-driven antagonism of apoptosis, Mol. Cancer, 10, 26, doi: 10.1186/1476-4598-10-26.

57. Wang, T. H., Lin, Y. H., Yang, S. C., Chang, P. C., Wang, T. C., and Chen, C. Y. (2017) Tid1-S regulates the mitochondrial localization of EGFR in non-small cell lung carcinoma, Oncogenesis, 6, e361, doi: 10.1038/oncsis.2017.62.

58. Che, T. F., Lin, C. W., Wu, Y. Y., Chen, Y. J., Han, C. L., Chang, Y. L., Wu, C. T., Hsiao, T. H., Hong, T. M., and Yang, P. C. (2015) Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC, Oncotarget, 6, 37349-37366, doi: 10.18632/oncotarget.5736.

59. Hsu, S. C., and Hung, M. C. (2007) Characterization of a novel tripartite nuclear localization sequence in the EGFR family, J. Biol. Chem., 282, 10432-10440, doi: 10.1074/jbc.M610014200.

60. Shah, P., Chaumet, A., Royle, S. J., and Bard, F. A. (2019) The NAE pathway: autobahn to the nucleus for cell surface receptors, Cells, 8, doi: 10.3390/cells8080915.

61. Lo, H. W., Ali-Seyed, M., Wu, Y., Bartholomeusz, G., Hsu, S. C., and Hung, M. C. (2006) Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1, J. Cell Biochem., 98, 1570-1583, doi: 10.1002/jcb.20876.

62. De Angelis Campos, A. C., Rodrigues, M. A., de Andrade, C., de Goes, A. M., Nathanson, M. H., and Gomes, D. A. (2011) Epidermal growth factor receptors destined for the nucleus are internalized via a clathrin-dependent pathway, Biochem. Biophys. Res. Commun., 412, 341-346, doi: 10.1016/j.bbrc.2011.07.100.

63. Lo, H. W. (2010) Nuclear mode of the EGFR signaling network: biology, prognostic value, and therapeutic implications, Discov. Med., 10, 44-51.

64. Faria, J. A. Q. A., de Andrade, C., Goes, A. M., Rodrigues, M. A., and Gomes, D. A. (2016) Effects of different ligands on epidermal growth factor receptor (EGFR) nuclear translocation, Biochem. Biophys. Res. Commun., 478, 39-45, doi: 10.1016/j.bbrc.2016.07.097.

65. Han, W., and Lo, H. W. (2012) Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations, Cancer Lett., 318, 124-134, doi: 10.1016/j.canlet.2012.01.011.

66. Wang, Y. N., Yamaguchi, H., Hsu, J. M., and Hung, M. C. (2010) Nuclear trafficking of the epidermal growth factor receptor family membrane proteins, Oncogene, 29, 3997-4006, doi: 10.1038/onc.2010.157.

67. Wang, Y. N., Yamaguchi, H., Huo, L., Du, Y., Lee, H. J., Lee, H. H., Wang, H., Hsu, J. M., and Hung, M. C. (2010) The translocon Sec61beta localized in the inner nuclear membrane transports membrane-embedded EGF receptor to the nucleus, J. Biol. Chem., 285, 38720-38729, doi: 10.1074/jbc.M110.158659.

68. Liao, H. J., and Carpenter, G. (2007) Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression, Mol. Biol. Cell, 18, 1064-1072, doi: 10.1091/mbc.e06-09-0802.

69. Chaumet, A., Wright, G. D., Seet, S. H., Tham, K. M., Gounko, N. V., and Bard, F. (2015) Nuclear envelope-associated endosomes deliver surface proteins to the nucleus, Nat. Commun., 6, 8218, doi: 10.1038/ncomms9218.

70. Chia, P. L., Scott, A. M., and John, T. (2019) Epidermal growth factor receptor (EGFR)-targeted therapies in mesothelioma, Expert Opin. Drug Deliv., 16, 441-451, doi: 10.1080/17425247.2019.1598374.

71. Franovic, A., Gunaratnam, L., Smith, K., Robert, I., Patten, D., and Lee, S. (2007) Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer, Proc. Natl. Acad. Sci. USA, 104, 13092-13097, doi: 10.1073/pnas.0702387104.

72. Liu, X., Wang, P., Zhang, C., and Ma, Z. (2017) Epidermal growth factor receptor (EGFR): a rising star in the era of precision medicine of lung cancer, Oncotarget, 8, 50209-50220, doi: 10.18632/oncotarget.16854.

73. Grandis, J. R., and Tweardy, D. J. (1993) Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer, Cancer Res., 53, 3579-3584.

74. Atkins, D., Reiffen, K. A., Tegtmeier, C. L., Winther, H., Bonato, M. S., and Storkel, S. (2004) Immunohisto-chemical detection of EGFR in paraffin-embedded tumor tissues: variation in staining intensity due to choice of fixative and storage time of tissue sections, J. Histochem. Cytochem., 52, 893-901, doi: 10.1369/jhc.3A6195.2004.

75. Yen, L. C., Uen, Y. H., Wu, D. C., Lu, C. Y., Yu, F. J.,Wu, I. C., Lin, S. R., and Wang, J. Y. (2010) Activating KRAS mutations and overexpression of epidermal growth factor receptor as independent predictors in metastatic colo-rectal cancer patients treated with cetuximab, Ann. Surg., 251, 254-260, doi: 10.1097/SLA.0b013e3181bc9d96.

76. Lee, H. J., Xu, X., Choe, G., Chung, D. H., Seo, J. W., Lee, J. H., Lee, C. T., Jheon, S., Sung, S. W., and Chung, J. H. (2010) Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas: comparison of four commercially available antibodies by immunohistochemistry and fluorescence in situ hybridization study, Lung Cancer, 68, 375-382, doi: 10.1016/j.lungcan.2009.07.014.

77. Gatalica, Z., Millis, S. Z., Vranic, S., Bender, R., Basu, G. D., Voss, A., and Von Hoff, D. D. (2014) Comprehensive tumor profiling identifies numerous biomarkers of drug response in cancers of unknown primary site: analysis of 1806 cases, Oncotarget, 5, 12440-12447, doi: 10.18632/oncotarget.2574.

78. Verhaak, R. G., Hoadley, K. A., Purdom, E., Wang, V., Qi, Y., et al. (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1, Cancer Cell, 17, 98-110.

79. Herbst, R. S., and Shin, D. M. (2002) Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy, Cancer, 94, 1593-1611, doi: 10.1002/cncr.10372.

80. Kalyankrishna, S., and Grandis, J. R. (2006) Epidermal growth factor receptor biology in head and neck cancer, J. Clin. Oncol., 24, 2666-2672, doi: 10.1200/JCO.2005.04.8306.

81. Chua, D. T., Nicholls, J. M., Sham, J. S., and Au, G. K. (2004) Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy, Int. J. Radiat. Oncol. Biol. Phys., 59, 11-20, doi: 10.1016/j.ijrobp.2003.10.038.

82. Wei, Q., Chen, L., Sheng, L., Nordgren, H., Wester, K., and Carlsson, J. (2007) EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases, Int. J. Oncol., 31, 493-499.

83. Grobe, A., Eichhorn, W., Fraederich, M., Kluwe, L., Vashist, Y., Wikner, J., Smeets, R., Simon, R., Sauter, G., Heiland, M., and Blessmann, M. (2014) Immunohistochemical and FISH analysis of EGFR and its prognostic value in patients with oral squamous cell carcinoma, J. Oral. Pathol. Med., 43, 205-210, doi: 10.1111/jop.12111.

84. Wang, X., Niu, H., Fan, Q., Lu, P., Ma, C., Liu, W., Liu, Y., Li, W., Hu, S., Ling, Y., Guo, L., Ying, J., and Huang, J. (2016) Predictive value of EGFR overexpression and gene amplification on icotinib efficacy in patients with advanced esophageal squamous cell carcinoma, Oncotarget, 7, 24744-24751, doi: 10.18632/oncotarget.8271.

85. Politi, A., Tsiambas, E., Mastronikolis, N. S., Peschos, D., Asproudis, I., Kyrodimos, E., Armata, I. E., Chrysovergis, A., Asimakopoulos, A., Papanikolaou, V. S., Batistatou, A., and Ragos, V. (2019) Combined EGFR/ALK expression analysis in laryngeal squamous cell carcinoma, In Vivo, 33, 815-819, doi: 10.21873/invivo.11544.

86. Schrevel, M., Gorter, A., Kolkman-Uljee, S. M., Trimbos, J. B., Fleuren, G. J., and Jordanova, E. S. (2011) Molecular mechanisms of epidermal growth factor receptor overexpression in patients with cervical cancer, Mod. Pathol., 24, 720-728, doi: 10.1038/modpathol.2010.239.

87. Gui, T., and Shen, K. (2012) The epidermal growth factor receptor as a therapeutic target in epithelial ovarian cancer, Cancer Epidemiol., 36, 490-496, doi: 10.1016/j.canep.2012.06.005.

88. Tian, W. J., Huang, M. L., Qin, Q. F., Chen, Q., Fang, K., and Wang, P. L. (2016) Prognostic impact of epidermal growth factor receptor overexpression in patients with cervical cancer: a meta-analysis, PLoS One, 11, e0158787, doi: 10.1371/journal.pone.0158787.

89. Li, Q., Tang, Y., Cheng, X., Ji, J., Zhang, J., and Zhou, X. (2014) EGFR protein expression and gene amplification in squamous intraepithelial lesions and squamous cell carcinomas of the cervix, Int. J. Clin. Exp. Pathol., 7, 733-741.

90. Rokita, M., Stec, R., Bodnar, L., Charkiewicz, R., Korniluk, J., Smoter, M., Cichowicz, M., Chyczewski, L., Niklinski, J., Kozlowski, W., and Szczylik, C. (2013) Overexpression of epidermal growth factor receptor as a prognostic factor in colorectal cancer on the basis of the Allred scoring system, Onco. Targets Ther., 6, 967-976, doi: 10.2147/OTT.S42446.

91. Yun, S., Kwak, Y., Nam, S. K., Seo, A. N., Oh, H. K., Kim, D. W., Kang, S. B., and Lee, H. S. (2018) Ligand-independent epidermal growth factor receptor overexpression correlates with poor prognosis in colorectal cancer, Cancer Res. Treat., 50, 1351-1361, doi: 10.4143/crt.2017.487.

92. Huang, C. W., Chen, Y. T., Tsai, H. L., Yeh, Y. S., Su, W. C., Ma, C. J., Tsai, T. N., and Wang, J. Y. (2017) EGFR expression in patients with stage III colorectal cancer after adjuvant chemotherapy and on cancer cell function, Oncotarget, 8, 114663-114676, doi: 10.18632/oncotarget.23072.

93. Grapa, C. M., Mocan, T., Gonciar, D., Zdrehus, C., Mosteanu, O., Pop, T., and Mocan, L. (2019) Epidermal growth factor receptor and its role in pancreatic cancer treatment mediated by nanoparticles, Int. J. Nanomedicine, 14, 9693-9706, doi: 10.2147/IJN.S226628.

94. Cook, N., Frese, K. K., and Moore, M. (2014) Assessing the role of the EGF receptor in the development and progression of pancreatic cancer, Gastrointest Cancer, 4, 23-37.

95. Karandish, F., and Mallik, S. (2016) Biomarkers and targeted therapy in pancreatic cancer, Biomarkers Cancer, 8, BIC-S34414.

96. Park, S. J., Gu, M. J., Lee, D. S., Yun, S. S., Kim, H. J., and Choi, J. H. (2015) EGFR expression in pancreatic intraepithelial neoplasia and ductal adenocarcinoma, Int. J. Clin. Exp. Pathol., 8, 8298-8304.

97. Gonzalez-Conchas, G. A., Rodriguez-Romo, L., Hernandez-Barajas, D., Gonzalez-Guerrero, J. F., Rodriguez-Fernandez, I. A., Verdines-Perez, A., Templeton, A. J., Ocana, A., Seruga, B., Tannock, I. F., Amir, E., and Vera-Badillo, F. E. (2018) Epidermal growth factor receptor overexpression and outcomes in early breast cancer: a systematic review and a meta-analysis, Cancer Treat. Rev., 62, 1-8, doi: 10.1016/j.ctrv.2017.10.008.

98. Sheng, Q., and Liu, J. (2011) The therapeutic potential of targeting the EGFR family in epithelial ovarian cancer, Br. J. Cancer, 104, 1241-1245, doi: 10.1038/bjc.2011.62.

99. Wang, K., Li, D., and Sun, L. (2016) High levels of EGFR expression in tumor stroma are associated with aggressive clinical features in epithelial ovarian cancer, Onco Targets Ther., 9, 377-386, doi: 10.2147/OTT.S96309.

100. Perren, T. J. (2016) Mucinous epithelial ovarian carcinoma, Ann. Oncol., 27 Suppl. 1, i53-i57, doi: 10.1093/annonc/mdw087.

101. Shinojima, N., Tada, K., Shiraishi, S., Kamiryo, T., Kochi, M., Nakamura, H., Makino, K., Saya, H., Hirano, H., Kuratsu, J., Oka, K., Ishimaru, Y., and Ushio, Y. (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme, Cancer Res., 63, 6962-6970.

102. Zhao, L. L., Xu, K. L., Wang, S. W., Hu, B. L., and Chen, L. R. (2012) Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas, Histopathology, 61, 726-736, doi: 10.1111/j.1365-2559.2012.04354.x.

103. Wang, X., Zhang, S., MacLennan, G. T., Eble, J. N., Lopez-Beltran, A., Yang, X. J., Pan, C. X., Zhou, H., Montironi, R., and Cheng, L. (2007) Epidermal growth factor receptor protein expression and gene amplification in small cell carcinoma of the urinary bladder, Clin. Cancer Res., 13, 953-957, doi: 10.1158/1078-0432.CCR-06-2167.

104. Chaux, A., Cohen, J. S., Schultz, L., Albadine, R., Jadallah, S., Murphy, K. M., Sharma, R., Schoenberg, M. P., and Netto, G. J. (2012) High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues, Hum. Pathol., 43, 1590-1595, doi: 10.1016/j.humpath.2011.11.016.

105. Carlsson, J., Wester, K., De La Torre, M., Malmstrom, P. U., and Gardmark, T. (2015) EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides, Radiol. Oncol., 49, 50-58, doi: 10.2478/raon-2014-0015.

106. Girard, N. (2010) Thymic tumors: relevant molecular data in the clinic, J. Thorac. Oncol., 5, S291-S295, doi: 10.1097/JTO.0b013e3181f209b9.

107. Rusch, V. W., Klimstra, D. S., and Venkatraman, E. S. (1996) Molecular markers help characterize neuroendocrine lung tumors, Ann. Thorac. Surg., 62, 798-809, doi: 10.1016/s0003-4975(96)00435-3.

108. Srirajaskanthan, R., Shah, T., Watkins, J., Marelli, L., Khan, K., and Caplin, M. E. (2010) Expression of the HER-1-4 family of receptor tyrosine kinases in neuroendocrine tumours, Oncol. Rep., 23, 909-915, doi: 10.3892/or_00000714.

109. London, M., and Gallo, E. (2020) Epidermal growth factor receptor (EGFR) involvement in epithelial-derived cancers and its current antibody-based immunotherapies, Cell Biol. Int., 44, 1267-1282, doi: 10.1002/cbin.11340.

110. Cunningham, D., Humblet, Y., Siena, S., Khayat, D., Bleiberg, H., Santoro, A., Bets, D., Mueser, M., Harstrick, A., Verslype, C., Chau, I., and Van Cutsem, E. (2004) Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer, N. Engl. J. Med., 351, 337-345, doi: 10.1056/NEJMoa033025.

111. Trivedi, S., Srivastava, R. M., Concha-Benavente, F., Ferrone, S., Garcia-Bates, T. M., Li, J., and Ferris, R. L. (2016) Anti-EGFR targeted monoclonal antibody isotype influences antitumor cellular immunity in head and neck cancer patients, Clin. Cancer Res., 22, 5229-5237, doi: 10.1158/1078-0432.CCR-15-2971.

112. Cohenuram, M., and Saif, M. W. (2007) Panitumumab the first fully human monoclonal antibody: from the bench to the clinic, Anticancer Drugs, 18, 7-15, doi: 10.1097/CAD.0b013e32800feecb.

113. Thatcher, N., Hirsch, F. R., Luft, A. V., Szczesna, A., Ciuleanu, T. E., Dediu, M., Ramlau, R., Galiulin, R. K., Balint, B., Losonczy, G., Kazarnowicz, A., Park, K., Schumann, C., Reck, M., Depenbrock, H., Nanda, S., Kruljac-Letunic, A., Kurek, R., Paz-Ares, L., and Socinski, M. A. (2015) Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial, Lancet Oncol., 16, 763-774, doi: 10.1016/S1470-2045(15)00021-2.

114. Li, J., and Yan, H. (2018) Skin toxicity with anti-EGFR monoclonal antibody in cancer patients: a meta-analysis of 65 randomized controlled trials, Cancer Chemother. Pharmacol., 82, 571-583, doi: 10.1007/s00280-018-3644-2.

115. Boland, W. K., and Bebb, G. (2009) Nimotuzumab: a novel anti-EGFR monoclonal antibody that retains anti-EGFR activity while minimizing skin toxicity, Expert Opin. Biol. Ther., 9, 1199-1206, doi: 10.1517/14712590903110709.

116. Garrido, G., Tikhomirov, I. A., Rabasa, A., Yang, E., Gracia, E., Iznaga, N., Fernandez, L. E., Crombet, T., Kerbel, R. S., and Perez, R. (2011) Bivalent binding by intermediate affinity of nimotuzumab: a contribution to explain antibody clinical profile, Cancer Biol. Ther., 11, 373-382, doi: 10.4161/cbt.11.4.14097.

117. Ciardiello, F., and Tortora, G. (2008) EGFR antagonists in cancer treatment, N. Engl. J. Med., 358, 1160-1174, doi: 10.1056/NEJMra0707704.

118. Therkildsen, C., Bergmann, T. K., Henrichsen-Schnack, T., Ladelund, S., and Nilbert, M. (2014) The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis, Acta Oncol., 53, 852-864, doi: 10.3109/0284186X.2014.895036.

119. Lu, Y., Zhao, X., Liu, Q., Li, C., Graves-Deal, R., Cao, Z., Singh, B., Franklin, J. L., Wang, J., Hu, H., Wei, T., Yang, M., Yeatman, T. J., Lee, E., Saito-Diaz, K., Hinger, S., Patton, J. G., Chung, C. H., Emmrich, S., Klusmann, J. H., Fan, D., and Coffey, R. J. (2017) lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/beta-catenin signaling, Nat. Med., 23, 1331-1341, doi: 10.1038/nm.4424.

120. Misale, S., Yaeger, R., Hobor, S., Scala, E., Janakiraman, M., et al. (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer, Nature, 486, 532-536, doi: 10.1038/nature11156.

121. Siravegna, G., Mussolin, B., Buscarino, M., Corti, G., Cassingena, A., et al. (2015) Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients, Nat. Med., 21, 795-801, doi: 10.1038/nm.3870.

122. Roskoski, R., Jr. (2020) Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update, Pharmacol. Res., 152, 104609, doi: 10.1016/j.phrs.2019.104609.

123. Yang, J. J., Zhou, C., Huang, Y., Feng, J., Lu, S., Song, Y., Huang, C., Wu, G., Zhang, L., Cheng, Y., Hu, C., Chen, G., Zhang, L., Liu, X., Yan, H. H., Tan, F. L., Zhong, W., and Wu, Y. L. (2017) Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial, Lancet Respir. Med., 5, 707-716, doi: 10.1016/S2213-2600(17)30262-X.

124. Mok, T. S., Wu, Y. L., Thongprasert, S., Yang, C. H., Chu, D. T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., Nishiwaki, Y., Ohe, Y., Yang, J. J., Chewaskulyong, B., Jiang, H., Duffield, E. L., Watkins, C. L., Armour, A. A., and Fukuoka, M. (2009) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, N. Engl. J. Med., 361, 947-957, doi: 10.1056/NEJMoa0810699.

125. Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., Akhavanfard, S., Heist, R. S., Temel, J., Christensen, J. G., Wain, J. C., Lynch, T. J., Vernovsky, K., Mark, E. J., Lanuti, M., Iafrate, A. J., Mino-Kenudson, M., and Engelman, J. A. (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors, Sci. Transl. Med., 3, 75ra26, doi: 10.1126/scitranslmed.3002003.

126. Pao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., and Varmus, H. (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain, PLoS Med., 2, e73, doi: 10.1371/journal.pmed.0020073.

127. Murtuza, A., Bulbul, A., Shen, J. P., Keshavarzian, P., Woodward, B. D., Lopez-Diaz, F. J., Lippman, S. M., and Husain, H. (2019) Novel third-generation EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer, Cancer Res., 79, 689-698, doi: 10.1158/0008-5472.CAN-18-1281.

128. Soria, J. C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T., Okamoto, I., Zhou, C., Cho, B. C., Cheng, Y., Cho, E. K., Voon, P. J., Planchard, D., Su, W. C., Gray, J. E., Lee, S. M., Hodge, R., Marotti, M., Rukazenkov, Y., and Ramalingam, S. S. (2018) Osimer-tinib in untreated EGFR-mutated advanced non-small-cell lung cancer, N. Engl. J. Med., 378, 113-125, doi: 10.1056/NEJMoa1713137.

129. Ramalingam, S. S., Vansteenkiste, J., Planchard, D., Cho, B. C., Gray, J. E., Ohe, Y., Zhou, C., Reungwetwattana, T., Cheng, Y., Chewaskulyong, B., Shah, R., Cobo, M., Lee, K. H., Cheema, P., Tiseo, M., John, T., Lin, M.C., Imamura, F., Kurata, T., Todd, A., Hodge, R., Saggese, M., Rukazenkov, Y., and Soria, J. C. (2020) Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC, N. Engl. J. Med., 382, 41-50, doi: 10.1056/NEJMoa1913662.

130. Nagano, T., Tachihara, M., and Nishimura, Y. (2018) Mechanism of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors and a potential treatment strategy, Cells, 7, doi: 10.3390/cells7110212.

131. Li, R., Zhou, X., Yao, H., and Li, L. (2020) Four generations of EGFR TKIs associated with different pathogenic mutations in non-small cell lung carcinoma, J. Drug Target, 1-12, doi: 10.1080/1061186X.2020.1737934.

132. Vyse, S., and Huang, P. H. (2019) Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer, Signal. Transduct. Target Ther., 4, 5, doi: 10.1038/s41392-019-0038-9.

133. Sordella, R., Bell, D. W., Haber, D. A., and Settleman, J. (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways, Science, 305, 1163-1167, doi: 10.1126/science.1101637.

134. Oxnard, G. R., Hu, Y., Mileham, K. F., Husain, H., Costa, D. B., Tracy, P., Feeney, N., Sholl, L. M., Dahlberg, S. E., Redig, A. J., Kwiatkowski, D. J., Rabin, M. S., Paweletz, C. P., Thress, K. S., and Janne, P. A. (2018) Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib, JAMA Oncol., 4, 1527-1534, doi: 10.1001/jamaoncol.2018.2969.

135. Piotrowska, Z., Isozaki, H., Lennerz, J. K., Gainor, J. F., Lennes, I. T., Zhu, V. W., Marcoux, N., Banwait, M. K., Digumarthy, S. R., Su, W., Yoda, S., Riley, A. K., Nangia, V., Lin, J. J., Nagy, R. J., Lanman, R. B., Dias-Santagata, D., Mino-Kenudson, M., Iafrate, A. J., Heist, R. S., Shaw, A. T., Evans, E. K., Clifford, C., Ou, S. I., Wolf, B., Hata, A. N., and Sequist, L. V. (2018) Landscape of acquired resistance to osimertinib in EGFR-mutant NSCLC and clinical validation of combined EGFR and RET inhibition with osimertinib and BLU-667 for acquired RET fusion, Cancer Discov., 8, 1529-1539, doi: 10.1158/2159-8290.CD-18-1022.

136. Wang, Q., Yang, S., Wang, K., and Sun, S. Y. (2019) MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer, J. Hematol. Oncol., 12, 63, doi: 10.1186/s13045-019-0759-9.

137. Terai, H., Soejima, K., Yasuda, H., Nakayama, S., Hamamoto, J., Arai, D., Ishioka, K., Ohgino, K., Ikemura, S., Sato, T., Yoda, S., Satomi, R., Naoki, K., and Betsuyaku, T. (2013) Activation of the FGF2-FGFR1 autocrine pathway: a novel mechanism of acquired resistance to gefitinib in NSCLC, Mol. Cancer Res., 11, 759-767, doi: 10.1158/1541-7786.MCR-12-0652.

138. Schoenfeld, A. J., Chan, J. M., Kubota, D., Sato, H., Rizvi, H., Daneshbod, Y., Chang, J. C., Paik, P. K., Offin, M., Arcila, M. E., Davare, M. A., Shinde, U., Pe’er, D., Rekhtman, N., Kris, M. G., Somwar, R., Riely, G. J., Ladanyi, M., and Yu, H. A. (2020) Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer, Clin. Cancer Res., 26, 2654-2663, doi: 10.1158/1078-0432.CCR-19-3563.

139. Zhu, V. W., Klempner, S. J., and Ou, S. I. (2019) Receptor tyrosine kinase fusions as an actionable resistance mechanism to EGFR TKIs in EGFR-mutant non-small-cell lung cancer, Trends Cancer, 5, 677-692, doi: 10.1016/j.trecan.2019.09.008.

140. Cheng, N., Cai, W., Ren, S., Li, X., Wang, Q., Pan, H., Zhao, M., Li, J., Zhang, Y., Zhao, C., Chen, X., Fei, K., Zhou, C., and Hirsch, F. R. (2015) Long non-coding RNA UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer, Oncotarget, 6, 23582-23593, doi: 10.18632/oncotarget.4361.

141. Lee, J. K., Lee, J., Kim, S., Kim, S., Youk, J., Park, S., An, Y., Keam, B., Kim, D. W., Heo, D. S., Kim, Y. T., Kim, J. S., Kim, S. H., Lee, J. S., Lee, S. H., Park, K., Ku, J. L., Jeon, Y. K., Chung, D. H., Park, P. J., Kim, J., Kim, T. M., and Ju, Y. S. (2017) Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas, J. Clin. Oncol., 35, 3065-3074, doi: 10.1200/JCO.2016.71.9096.

142. Heitzer, E., Ulz, P., and Geigl, J. B. (2015) Circulating tumor DNA as a liquid biopsy for cancer, Clin. Chem., 61, 112-123, doi: 10.1373/clinchem.2014.222679.

143. Yohe, S., and Thyagarajan, B. (2017) Review of clinical next-generation sequencing, Arch. Pathol. Lab. Med., 141, 1544-1557, doi: 10.5858/arpa.2016-0501-RA.

144. Greaves, M., and Maley, C. C. (2012) Clonal evolution in cancer, Nature, 481, 306-313, doi: 10.1038/nature10762.

145. McGranahan, N., and Swanton, C. (2017) Clonal heterogeneity and tumor evolution: past, present, and the future, Cell, 168, 613-628, doi: 10.1016/j.cell.2017.01.018.

146. Negrini, S., Gorgoulis, V. G., and Halazonetis, T. D. (2010) Genomic instability – an evolving hallmark of cancer, Nat. Rev. Mol. Cell Biol., 11, 220-228, doi: 10.1038/nrm2858.

147. Jaramillo, M. L., Leon, Z., Grothe, S., Paul-Roc, B., Abulrob, A., and O’Connor, M. M. (2006) Effect of the anti-receptor ligand-blocking 225 monoclonal antibody on EGF receptor endocytosis and sorting, Exp. Cell Res., 312, 2778-2790, doi: 10.1016/j.yexcr.2006.05.008.

148. Liao, H. J., and Carpenter, G. (2009) Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor, Cancer Res., 69, 6179-6183, doi: 10.1158/0008-5472.CAN-09-0049.

149. Bhattacharyya, S., Singh, R. D., Pagano, R., Robertson, J. D., Bhattacharya, R., and Mukherjee, P. (2012) Switching the targeting pathways of a therapeutic antibody by nanodesign, Angew. Chem. Int. Ed. Engl., 51, 1563-1567, doi: 10.1002/anie.201105432.

150. Kim, D. H., Kim, D. K., Zhou, K., Park, S., Kwon, Y., Jeong, M. G., Lee, N. K., and Ryu, S. H. (2017) Single particle tracking-based reaction progress kinetic analysis reveals a series of molecular mechanisms of cetuximab-induced EGFR processes in a single living cell, Chem. Sci., 8, 4823-4832, doi: 10.1039/c7sc01159h.

151. Tolmachev, V., and Orlova, A. (2020) Affibody molecules as targeting vectors for PET imaging, Cancers (Basel), 12, doi: 10.3390/cancers12030651.

152. Gцstring, L., Chew, M. T., Orlova, A., Hoiden-Guthenberg, I., Wennborg, A., Carlsson, J., and Frejd, F. Y. (2010) Quantification of internalization of EGFR-binding Affibody molecules: methodological aspects, Int. J. Oncol., 36, 757-763, doi: 10.3892/ijo_00000551.

153. Genta, I., Chiesa, E., Colzani, B., Modena, T., Conti, B., and Dorati, R. (2017) GE11 peptide as an active targeting agent in antitumor therapy: a minireview, Pharmaceutics, 10, doi: 10.3390/pharmaceutics10010002.

154. Li, N., Nguyen, H. H., Byrom, M., and Ellington, A. D. (2011) Inhibition of cell proliferation by an anti-EGFR aptamer, PLoS One, 6, e20299, doi: 10.1371/journal.pone.0020299.

155. Maeda, H., Wu, J., Sawa, T., Matsumura, Y., and Hori, K. (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review, J. Control. Release, 65, 271-284, doi: 10.1016/s0168-3659(99)00248-5.

156. Danhier, F. (2016) To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine? J. Control. Release, 244, 108-121, doi: 10.1016/j.jconrel.2016.11.015.

157. Golombek, S. K., May, J. N., Theek, B., Appold, L., Drude, N., Kiessling, F., and Lammers, T. (2018) Tumor targeting via EPR: strategies to enhance patient responses, Adv. Drug Deliv. Rev., 130, 17-38, doi: 10.1016/j.addr.2018.07.007.

158. Park, J., Choi, Y., Chang, H., Um, W., Ryu, J. H., and Kwon, I. C. (2019) Alliance with EPR effect: combined strategies to improve the EPR effect in the tumor microenvironment, Theranostics, 9, 8073-8090, doi: 10.7150/thno.37198.

159. Mamot, C., Ritschard, R., Wicki, A., Stehle, G., Dieterle, T., Bubendorf, L., Hilker, C., Deuster, S., Herrmann, R., and Rochlitz, C. (2012) Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study, Lancet Oncol., 13, 1234-1241, doi: 10.1016/S1470-2045(12)70476-X.

160. Mamot, C., Drummond, D. C., Noble, C. O., Kallab, V., Guo, Z., Hong, K., Kirpotin, D. B., and Park, J. W. (2005) Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo, Cancer Res., 65, 11631-11638, doi: 10.1158/0008-5472.CAN-05-1093.

161. Pan, X., and Lee, R. J. (2007) Construction of anti-EGFR immunoliposomes via folate-folate binding protein affinity, Int. J. Pharm., 336, 276-283, doi: 10.1016/j.ijpharm.2006.12.007.

162. Pan, X., Wu, G., Yang, W., Barth, R. F., Tjarks, W., and Lee, R. J. (2007) Synthesis of cetuximab-immunoliposomes via a cholesterol-based membrane anchor for targeting of EGFR, Bioconjug. Chem., 18, 101-108, doi: 10.1021/bc060174r.

163. Vazquez-Becerra, H., Perez-Cardenas, E., Muniz-Hernandez, S., Izquierdo-Sanchez, V., and Medina, L. A. (2017) Characterization and in vitro evaluation of nimotuzumab conjugated with cisplatin-loaded liposomes, J. Liposome Res., 27, 274-282, doi: 10.1080/08982104.2016.1207665.

164. Petrilli, R., Eloy, J. O., Saggioro, F. P., Chesca, D. L., de Souza, M. C., Dias, M. V. S., daSilva, L. L. P., Lee, R. J., and Lopez, R. F. V. (2018) Skin cancer treatment effectiveness is improved by iontophoresis of EGFR-targeted liposomes containing 5-FU compared with subcutaneous injection, J. Control. Release, 283, 151-162, doi: 10.1016/j.jconrel.2018.05.038.

165. Broekgaarden, M., van Vught, R., Oliveira, S., Roovers, R. C., van Bergen en Henegouwen, P. M. P., Pieters, R. J., Van Gulik, T. M., Breukink, E., and Heger, M. (2016) Site-specific conjugation of single domain antibodies to liposomes enhances photosensitizer uptake and photodynamic therapy efficacy, Nanoscale, 8, 6490-6494, doi: 10.1039/c6nr00014b.

166. Zalba, S., Contreras, A. M., Merino, M., Navarro, I., de Ilarduya, C. T., Troconiz, I. F., Koning, G., and Garrido, M. J. (2016) EGF-liposomes promote efficient EGFR targeting in xenograft colocarcinoma model, Nanomedicine (Lond.), 11, 465-477, doi: 10.2217/nnm.15.208.

167. Jung, J., Jeong, S. Y., Park, S. S., Shin, S. H., Ju, E. J., Choi, J., Park, J., Lee, J. H., Kim, I., Suh, Y. A., Hwang, J. J., Kuroda, S., Lee, J. S., Song, S. Y., and Choi, E. K. (2015) A cisplatin-incorporated liposome that targets the epidermal growth factor receptor enhances radiotherapeutic efficacy without nephrotoxicity, Int. J. Oncol., 46, 1268-1274, doi: 10.3892/ijo.2014.2806.

168. Aggarwal, S., Gupta, S., Pabla, D., and Murthy, R. S. (2013) Gemcitabine-loaded PLGA-PEG immunonano-particles for targeted chemotherapy of pancreatic cancer, Cancer Nanotechnol., 4, 145-157, doi: 10.1007/s12645-013-0046-3.

169. Wöll, S., Bachran, C., Schiller, S., Schröder, M., Conrad, L., Swee, L. K., and Scherliess, R. (2018) Sortaggable liposomes: evaluation of reaction conditions for single-domain antibody conjugation by Sortase-A and targeting of CD11b(+) myeloid cells, Eur. J. Pharm. Biopharm., 133, 138-150, doi: 10.1016/j.ejpb.2018.09.017.

170. Wang, Y. P., Liu, I. J., Chung, M. J., and Wu, H. C. (2020) Novel anti-EGFR scFv human antibody-conjugated immunoliposomes enhance chemotherapeutic efficacy in squamous cell carcinoma of head and neck, Oral Oncol., 106, 104689, doi: 10.1016/j.oraloncology.2020.104689.

171. Hsu, W. C., Cheng, C. N., Lee, T. W., and Hwang, J. J. (2015) Cytotoxic effects of PEGylated anti-EGFR immunoliposomes combined with doxorubicin and Rhenium-188 against cancer cells, Anticancer Res., 35, 4777-4788.

172. Haeri, A., Zalba, S., Ten Hagen, T. L., Dadashzadeh, S., and Koning, G. A. (2016) EGFR targeted thermosensitive liposomes: a novel multifunctional platform for simultaneous tumor targeted and stimulus responsive drug delivery, Colloids Surf. B Biointerfaces, 146, 657-669, doi: 10.1016/j.colsurfb.2016.06.012.

173. Kim, I. Y., Kang, Y. S., Lee, D. S., Park, H. J., Choi, E. K., Oh, Y. K., Son, H. J., and Kim, J. S. (2009) Antitumor activity of EGFR targeted pH-sensitive immunoliposomes encapsulating gemcitabine in A549 xenograft nude mice, J. Control. Release, 140, 55-60, doi: 10.1016/j.jconrel.2009.07.005.

174. Talelli, M., Oliveira, S., Rijcken, C. J., Pieters, E. H., Etrych, T., Ulbrich, K., van Nostrum, R. C., Storm, G., Hennink, W. E., and Lammers, T. (2013) Intrinsically active nanobody-modified polymeric micelles for tumor-targeted combination therapy, Biomaterials, 34, 1255-1260, doi: 10.1016/j.biomaterials.2012.09.064.

175. Gener, P., Gouveia, L. P., Sabat, G. R., de Sousa Rafael, D. F., Fort, N. B., Arranja, A., Fernandez, Y., Prieto, R. M., Ortega, J. S., Arango, D., Abasolo, I., Videira, M., and Schwartz, S., Jr. (2015) Fluorescent CSC models evidence that targeted nanomedicines improve treatment sensitivity of breast and colon cancer stem cells, Nanomedicine, 11, 1883-1892.

176. Kang, S. J., Jeong, H. Y., Kim, M. W., Jeong, I. H., Choi, M. J., You, Y. M., Im, C. S., Song, I. H., Lee, T. S., and Park, Y. S. (2018) Anti-EGFR lipid micellar nanoparticles co-encapsulating quantum dots and paclitaxel for tumor-targeted theranosis, Nanoscale, 10, 19338-19350, doi: 10.1039/c8nr05099f.

177. Mondal, G., Almawash, S., Chaudhary, A. K., and Mahato, R. I. (2017) EGFR-targeted cationic polymeric mixed micelles for codelivery of gemcitabine and miR-205 for treating advanced pancreatic cancer, Mol. Pharm., 14, 3121-3133, doi: 10.1021/acs.molpharmaceut.7b00355.

178. Kutty, R. V., Chia, S. L., Setyawati, M. I., Muthu, M. S., Feng, S. S., and Leong, D. T. (2015) In vivo and ex vivo proofs of concept that cetuximab conjugated vitamin E TPGS micelles increases efficacy of delivered docetaxel against triple negative breast cancer, Biomaterials, 63, 58-69, doi: 10.1016/j.biomaterials.2015.06.005.

179. Jiang, J., Chen, H., Yu, C., Zhang, Y., Chen, M., Tian, S., and Sun, C. (2015) The promotion of salinomycin delivery to hepatocellular carcinoma cells through EGFR and CD133 aptamers conjugation by PLGA nanoparticles, Nanomedicine (Lond.), 10, 1863-1879, doi: 10.2217/nnm.15.43.

180. Chen, J., Ouyang, J., Chen, Q., Deng, C., Meng, F., Zhang, J., Cheng, R., Lan, Q., and Zhong, Z. (2017) EGFR and CD44 dual-targeted multifunctional hyaluronic acid Nanogels boost protein delivery to ovarian and breast cancers in vitro and in vivo, ACS Appl. Mater. Interfaces., 9, 24140-24147, doi: 10.1021/acsami.7b06879.

181. Gao, J., Xia, Y., Chen, H., Yu, Y., Song, J., Li, W., Qian, W., Wang, H., Dai, J., and Guo, Y. (2014) Polymer-lipid hybrid nanoparticles conjugated with anti-EGF receptor antibody for targeted drug delivery to hepatocellular carcinoma, Nanomedicine (Lond.), 9, 279-293, doi: 10.2217/nnm.13.20.

182. Zhai, J., Luwor, R. B., Ahmed, N., Escalona, R., Tan, F. H., Fong, C., Ratcliffe, J., Scoble, J. A., Drummond, C. J., and Tran, N. (2018) Paclitaxel-loaded self-assembled lipid nanoparticles as targeted drug delivery systems for the treatment of aggressive ovarian cancer, ACS Appl. Mater. Interfaces, 10, 25174-25185, doi: 10.1021/acsami.8b08125.

183. Karra, N., Nassar, T., Ripin, A. N., Schwob, O., Borlak, J., and Benita, S. (2013) Antibody conjugated PLGA nanoparticles for targeted delivery of paclitaxel palmitate: efficacy and biofate in a lung cancer mouse model, Small, 9, 4221-4236, doi: 10.1002/smll.201301417.

184. Sreeranganathan, M., Uthaman, S., Sarmento, B., Mohan, C. G., Park, I. K., and Jayakumar, R. (2017) In vivo evaluation of cetuximab-conjugated poly(gamma-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts, Int. J. Nanomedicine, 12, 7165-7182, doi: 10.2147/IJN.S143529.

185. Patel, J., Amrutiya, J., Bhatt, P., Javia, A., Jain, M., and Misra, A. (2018) Targeted delivery of monoclonal antibody conjugated docetaxel loaded PLGA nanoparticles into EGFR overexpressed lung tumour cells, J. Microencapsul., 35, 204-217, doi: 10.1080/02652048.2018.1453560.

186. Wang, J. K., Zhou, Y. Y., Guo, S. J., Wang, Y. Y., Nie, C. J., Wang, H. L., Wang, J. L., Zhao, Y., Li, X. Y., and Chen, X. J. (2017) Cetuximab conjugated and doxorubicin loaded silica nanoparticles for tumor-targeting and tumor microenvironment responsive binary drug delivery of liver cancer therapy, Mater. Sci. Eng. C Mater. Biol. Appl., 76, 944-950, doi: 10.1016/j.msec.2017.03.131.

187. Sandoval, M. A., Sloat, B. R., Lansakara, P., Kumar, A., Rodriguez, B. L., Kiguchi, K., Digiovanni, J., and Cui, Z. (2012) EGFR-targeted stearoyl gemcitabine nanoparticles show enhanced anti-tumor activity, J. Control. Release, 157, 287-296, doi: 10.1016/j.jconrel.2011.08.015.

188. Bouras, A., Kaluzova, M., and Hadjipanayis, C. G. (2015) Radiosensitivity enhancement of radioresistant glioblastoma by epidermal growth factor receptor antibody-conjugated iron-oxide nanoparticles, J. Neurooncol., 124, 13-22, doi: 10.1007/s11060-015-1807-0.

189. Chen, C. H., Wu, Y. J., and Chen, J. J. (2016) Photo-thermal therapy of bladder cancer with Anti-EGFR antibody conjugated gold nanoparticles, Front. Biosci. (Landmark Ed.), 21, 1211-1221, doi: 10.2741/4451.

190. El-Sayed, I. H., Huang, X., and El-Sayed, M. A. (2006) Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles, Cancer Lett., 239, 129-135, doi: 10.1016/j.canlet.2005.07.035.

191. Rosenkranz, A. A., Slastnikova, T. A., Georgiev, G. P., Zalutsky, M. R., and Sobolev, A. S. (2020) Delivery systems exploiting natural cell transport processes of macromolecules for intracellular targeting of Auger electron emitters, Nucl. Med. Biol., 80-81, 45-56, doi: 10.1016/j.nucmedbio.2019.11.005.

192. Li, L., Quang, T. S., Gracely, E. J., Kim, J. H., Emrich, J. G., Yaeger, T. E., Jenrette, J. M., Cohen, S. C., Black, P., and Brady, L. W. (2010) A Phase II study of anti-epidermal growth factor receptor radioimmunotherapy in the treatment of glioblastoma multiforme, J. Neurosurg., 113, 192-198, doi: 10.3171/2010.2.JNS091211.

193. Emrich, J. G., Bender, H., Class, R., Eshleman, J., Miyamoto, C., and Brady, L. W. (1996) In vitro evaluation of iodine-125-labeled monoclonal antibody (MAb 425) in human high-grade glioma cells, Am. J. Clin. Oncol., 19, 601-608, doi: 10.1097/00000421-199612000-00015.

194. Reilly, R. M., Chen, P., Wang, J., Scollard, D., Cameron, R., and Vallis, K. A. (2006) Preclinical pharmacokinetic, biodistribution, toxicology, and dosimetry studies of 111In-DTPA-human epidermal growth factor: an Auger electron-emitting radiotherapeutic agent for epidermal growth factor receptor-positive breast cancer, J. Nucl. Med., 47, 1023-1031.

195. Panosa, C., Fonge, H., Ferrer-Batalle, M., Menendez, J. A., Massaguer, A., De Llorens, R., and Reilly, R. M. (2015) A comparison of non-biologically active truncated EGF (EGFt) and full-length hEGF for delivery of Auger electron-emitting 111In to EGFR-positive breast cancer cells and tumor xenografts in athymic mice, Nucl. Med. Biol., 42, 931-938, doi: 10.1016/j.nucmedbio.2015.08.003.

196. Vallis, K. A., Reilly, R. M., Scollard, D., Merante, P., Brade, A., Velauthapillai, S., Caldwell, C., Chan, I., Freeman, M., Lockwood, G., Miller, N. A., Cornelissen, B., Petronis, J., and Sabate, K. (2014) Phase I trial to evaluate the tumor and normal tissue uptake, radiation dosimetry and safety of (111)In-DTPA-human epidermal growth factor in patients with metastatic EGFR-positive breast cancer, Am. J. Nucl. Med. Mol. Imaging, 4, 181-192.

197. Cornelissen, B., Waller, A., Able, S., and Vallis, K. A. (2013) Molecular radiotherapy using cleavable radioimmunoconjugates that target EGFR and gammaH2AX, Mol. Cancer Ther., 12, 2472-2482, doi: 10.1158/1535-7163.MCT-13-0369.

198. Rosenkranz, A. A., Ulasov, A. V., Slastnikova, T. A., Khramtsov, Y. V., and Sobolev, A. S. (2014) Use of intracellular transport processes for targeted drug delivery into a specified cellular compartment, Biochemistry (Moscow), 79, 928-946, doi: 10.1134/S0006297914090090.

199. Sobolev, A. S. (2009) Modular nanotransporters of anticancer drugs conferring cell specificity and higher efficiency, Biochemistry (Moscow), 74, 1567-1574, doi: 10.1134/s0006297909130094.

200. Sobolev, A. S., Aliev, R. A., and Kalmykov, S. N. (2016) Radionuclides emitting short-range particles and modular nanotransporters for their delivery to target cancer cells, Rus. Chem. Rev., 85, 1011-1032.

201. Sobolev, A. S. (2018) Modular nanotransporters for nuclear-targeted delivery of Auger electron emitters, Front. Pharmacol., 9, 952, doi: 10.3389/fphar.2018.00952.

202. Gilyazova, D. G., Rosenkranz, A. A., Gulak, P. V., Lunin, V. G., Sergienko, O. V., Khramtsov, Y. V., Timofeyev, K. N., Grin, M. A., Mironov, A. F., Rubin, A. B., Georgiev, G. P., and Sobolev, A. S. (2006) Targeting cancer cells by novel engineered modular transporters, Cancer Res., 66, 10534-10540, doi: 10.1158/0008-5472.CAN-06-2393.

203. Slastnikova, T. A., Rosenkranz, A. A., Gulak, P. V., Schiffelers, R. M., Lupanova, T. N., Khramtsov, Y. V., Zalutsky, M. R., and Sobolev, A. S. (2012) Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery, Int. J. Nanomed., 7, 467-482, doi: 10.2147/IJN.S28249.

204. Slastnikova, T. A., Koumarianou, E., Rosenkranz, A. A., Vaidyanathan, G., Lupanova, T. N., Sobolev, A. S., and Zalutsky, M. R. (2012) Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I, EJNMMI Res., 2, 59, doi: 10.1186/2191-219X-2-59.

205. Koumarianou, E., Slastnikova, T. A., Pruszynski, M., Rosenkranz, A. A., Vaidyanathan, G., Sobolev, A. S., and Zalutsky, M. R. (2014) Radiolabeling and in vitro evaluation of (67)Ga-NOTA-modular nanotransporter – a potential Auger electron emitting EGFR-targeted radiotherapeutic, Nucl. Med. Biol., 41, 441-449, doi: 10.1016/j.nucmedbio.2014.03.026.

206. Slastnikova, T. A., Rosenkranz, A. A., Morozova, N. B., Vorontsova, M. S., Petriev, V. M., Lupanova, T. N., Ulasov, A. V., Zalutsky, M. R., Yakubovskaya, R. I., and Sobolev, A. S. (2017) Preparation, cytotoxicity, and in vivo antitumor efficacy of (111)In-labeled modular nanotransporters, Int. J. Nanomed., 12, 395-410, doi: 10.2147/IJN.S125359.

207. Rosenkranz, A. A., Slastnikova, T. A., Karmakova, T. A., Vorontsova, M. S., Morozova, N. B., Petriev, V. M., Abrosimov, A. S., Khramtsov, Y. V., Lupanova, T. N., Ulasov, A. V., Yakubovskaya, R. I., Georgiev, G. P., and Sobolev, A. S. (2018) Antitumor activity of Auger electron emitter 111In delivered by modular nanotransporter for treatment of bladder cancer with EGFR overexpression, Front. Pharmacol., 9, 1331, doi: 10.3389/fphar.2018.01331.

208. Karyagina, T. S., Ulasov, A. V., Slastnikova, T. A., Rosenkranz, A. A., Lupanova, T. N., Khramtsov, Y. V., Georgiev, G. P., and Sobolev, A. S. (2020) Targeted delivery of 111In into the nuclei of EGFR overexpressing cells via modular nanotransporters with anti-EGFR affibody, Front. Pharmacol., 11, 176, doi: 10.3389/fphar.2020.00176.

209. Li, S., Goins, B., Hrycushko, B. A., Phillips, W. T., and Bao, A. (2012) Feasibility of eradication of breast cancer cells remaining in postlumpectomy cavity and draining lymph nodes following intracavitary injection of radioactive immunoliposomes, Mol. Pharm., 9, 2513-2522, doi: 10.1021/mp300132f.

210. Song, H., Hedayati, M., Hobbs, R. F., Shao, C., Bruchertseifer, F., Morgenstern, A., Deweese, T. L., and Sgouros, G. (2013) Targeting aberrant DNA double-strand break repair in triple-negative breast cancer with alpha-particle emitter radiolabeled anti-EGFR antibody, Mol. Cancer Ther., 12, 2043-2054, doi: 10.1158/1535-7163.MCT-13-0108.

211. Pfost, B., Seidl, C., Autenrieth, M., Saur, D., Bruchertseifer, F., Morgenstern, A., Schwaiger, M., and Senekowitsch-Schmidtke, R. (2009) Intravesical alpha-radioimmunotherapy with 213Bi-anti-EGFR-mAb defeats human bladder carcinoma in xenografted nude mice, J. Nucl. Med., 50, 1700-1708, doi: 10.2967/jnumed.109.065961.

212. Fazel, J., Rotzer, S., Seidl, C., Feuerecker, B., Autenrieth, M., Weirich, G., Bruchertseifer, F., Morgenstern, A., and Senekowitsch-Schmidtke, R. (2015) Fractionated intra-vesical radioimmunotherapy with 213Bi-anti-EGFR-MAb is effective without toxic side-effects in a nude mouse model of advanced human bladder carcinoma, Cancer Biol. Ther., 16, 1526-1534, doi: 10.1080/15384047.2015.1071735.

213. Autenrieth, M. E., Seidl, C., Bruchertseifer, F., Horn, T., Kurtz, F., Feuerecker, B., D’Alessandria, C., Pfob, C., Nekolla, S., Apostolidis, C., Mirzadeh, S., Gschwend, J. E., Schwaiger, M., Scheidhauer, K., and Morgenstern, A. (2018) Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study, Eur. J. Nucl. Med. Mol. Imaging, 45, 1364-1371, doi: 10.1007/s00259-018-4003-6.

214. Milenic, D. E., Baidoo, K. E., Kim, Y. S., and Brechbiel, M. W. (2015) Evaluation of cetuximab as a candidate for targeted alpha-particle radiation therapy of HER1-positive disseminated intraperitoneal disease, MAbs, 7, 255-264, doi: 10.4161/19420862.2014.985160.

215. Zidenberg-Cherr, S., Parks, N. J., and Keen, C. L. (1987) Tissue and subcellular distribution of bismuth radiotracer in the rat: considerations of cytotoxicity and microdosimetry for bismuth radiopharmaceuticals, Radiat. Res., 111, 119-129.

216. Rosenkranz, A. A., Vaidyanathan, G., Pozzi, O. R., Lunin, V. G., Zalutsky, M. R., and Sobolev, A. S. (2008) Engineered modular recombinant transporters: application of new platform for targeted radiotherapeutic agents to alpha-particle emitting 211 At, Int. J. Radiat. Oncol. Biol. Phys., 72, 193-200, doi: 10.1016/j.ijrobp.2008.05.055.

217. Simon, N., and FitzGerald, D. (2016) Immunotoxin therapies for the treatment of epidermal growth factor receptor-dependent cancers, Toxins (Basel), 8, doi: 10.3390/toxins8050137.

218. Yang, Y., Tian, Z., Ding, Y., Li, X., Zhang, Z., Yang, L., Zhao, F., Ren, F., and Guo, R. (2018) EGFR-targeted immunotoxin exerts antitumor effects on esophageal cancers by increasing ROS accumulation and inducing apoptosis via inhibition of the Nrf2-Keap1 pathway, J. Immunol. Res., 2018, 1090287, doi: 10.1155/2018/1090287.

219. Deng, C., Xiong, J., Gu, X., Chen, X., Wu, S., Wang, Z., Wang, D., Tu, J., and Xie, J. (2017) Novel recombinant immunotoxin of EGFR specific nanobody fused with cucurmosin, construction and antitumor efficiency in vitro, Oncotarget, 8, 38568-38580, doi: 10.18632/oncotarget.16930.

220. Kim, J. S., Jun, S. Y., and Kim, Y. S. (2020) Critical issues in the development of immunotoxins for anticancer therapy, J. Pharm. Sci., 109, 104-115, doi: 10.1016/j.xphs.2019.10.037.

221. Sampson, J. H., Akabani, G., Archer, G. E., Berger, M. S., Coleman, R. E., Friedman, A. H., Friedman, H. S., Greer, K., Herndon, J. E., Kunwar, S., McLendon, R. E., Paolino, A., Petry, N. A., Provenzale, J. M., Reardon, D. A., Wong, T. Z., Zalutsky, M. R., Pastan, I., and Bigner, D. D. (2008) Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors, Neuro Oncol., 10, 320-329, doi: 10.1215/15228517-2008-012.

222. Chandramohan, V., Pegram, C. N., Piao, H., Szafranski, S. E., Kuan, C. T., Pastan, I. H., and Bigner, D. D. (2017) Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial, Appl. Microbiol. Biotechnol., 101, 2747-2766, doi: 10.1007/s00253-016-8063-x.

223. Zalutsky, M. R., Boskovitz, A., Kuan, C. T., Pegram, C. N., Ayriss, J., Wikstrand, C. J., Buckley, A. F., Lipp, E. S., Herndon, J. E., McLendon, R. E., and Bigner, D. D. (2012) Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors, Nucl. Med. Biol., 39, 23-34, doi: 10.1016/j.nucmedbio.2011.06.005.

224. Chandramohan, V., Bao, X., Keir, S. T., Pegram, C. N., Szafranski, S. E., Piao, H., Wikstrand, C. J., McLendon, R. E., Kuan, C. T., Pastan, I. H., and Bigner, D. D. (2013) Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy, Clin. Cancer Res., 19, 4717-4727, doi: 10.1158/1078-0432.CCR-12-3891.

225. Chandramohan, V., Bao, X., Yu, X., Parker, S., McDowall, C., Yu, Y. R., Healy, P., Desjardins, A., Gunn, M. D., Gromeier, M., Nair, S. K., Pastan, I. H., and Bigner, D. D. (2019) Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations, J. Immunother. Cancer, 7, 142, doi: 10.1186/s40425-019-0614-0.

226. Agostinis, P., Berg, K., Cengel, K. A., Foster, T. H., Girotti, A. W., Gollnick, S. O., Hahn, S. M., Hamblin, M. R., Juzeniene, A., Kessel, D., Korbelik, M., Moan, J., Mroz, P., Nowis, D., Piette, J., Wilson, B. C., and Golab, J. (2011) Photodynamic therapy of cancer: an update, CA Cancer J. Clin., 61, 250-281, doi: 10.3322/caac.20114.

227. Liang, H., Shin, D. S., Lee, Y. E., Nguyen, D. C., Trang, T. C., Pan, A. H., Huang, S. L., Chong, D. H., and Berns, M. W. (1998) Subcellular phototoxicity of 5-aminolaevulinic acid (ALA), Lasers Surg. Med., 22, 14-24, doi: 10.1002/(sici)1096-9101(1998)22:1<14::aid-lsm6>3.0.co;2-#.

228. Rosenkranz, A. A., Jans, D. A., and Sobolev, A. S. (2000) Targeted intracellular delivery of photosensitizers to enhance photodynamic efficiency, Immunol. Cell. Biol., 78, 452-464, doi: 10.1046/j.1440-1711.2000.00925.x.

229. Gilyazova, D. G., Rosenkranz, A. A., Gulak, P. V., Lunin, V. G., Sergienko, O. V., Grin, M. A., Mironov, A. F., Rubin, A. B., and Sobolev, A. S. (2006) Recombinant modular transporters on the basis of epidermal growth factor for targeted intracellular delivery of photosensitizers, Curr. Res. Laser Use Oncol.: 2000-2004, 5973, 59730E, doi: 10.1117/12.640049.

230. Gillenwater, A. M., Johnson, J. M., Curry, J. M., Kochuparambil, S. T., McDonald, D., Fidler, M., Stenson, K. M., Vasan, N. R., Razaq, M. A., and Campana, J. (2020) Survival following photoimmunotherapy in patients (Pts) with recurrent head and neck squamous cell carcinoma (rHNSCC), Int. J. Radiat. Oncol. Biol. Phys., 106, 1180-1180.

231. Fernandes, S. R. G., Fernandes, R., Sarmento, B., Pereira, P. M. R., and Tome, J. P. C. (2019) Photoimmunocon-jugates: novel synthetic strategies to target and treat cancer by photodynamic therapy, Org. Biomol. Chem., 17, 2579-2593, doi: 10.1039/c8ob02902d.

232. Harvey, T. J., Burdon, D., Steele, L., Ingram, N., Hall, G. D., Selby, P. J., Vile, R. G., Cooper, P. A., Shnyder, S. D., and Chester, J. D. (2010) Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor, Gene Ther., 17, 1000-1010, doi: 10.1038/gt.2010.45.

233. Urnauer, S., Muller, A. M., Schug, C., Schmohl, K. A., Tutter, M., Schwenk, N., Rodl, W., Morys, S., Ingrisch, M., Bertram, J., Bartenstein, P., Clevert, D. A., Wagner, E., and Spitzweg, C. (2017) EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases, Oncotarget, 8, 92195-92208, doi: 10.18632/oncotarget.21028.

234. Liang, Y., Peng, J., Li, N., Yu-Wai-Man, C., Wang, Q., Xu, Y., Wang, H., Tagalakis, A. D., and Du, Z. (2019) Smart nanoparticles assembled by endogenous molecules for siRNA delivery and cancer therapy via CD44 and EGFR dual-targeting, Nanomedicine, 15, 208-217, doi: 10.1016/j.nano.2018.09.018.

235. Bagley, S. J., and O’Rourke, D. M. (2020) Clinical investigation of CAR T cells for solid tumors: lessons learned and future directions, Pharmacol. Ther., 205, 107419, doi: 10.1016/j.pharmthera.2019.107419.

236. Westphal, M., Maire, C. L., and Lamszus, K. (2017) EGFR as a target for glioblastoma treatment: an unfulfilled promise, CNS Drugs, 31, 723-735, doi: 10.1007/s40263-017-0456-6.

237. Xu, M. J., Johnson, D. E., and Grandis, J. R. (2017) EGFR-targeted therapies in the post-genomic era, Cancer Metastasis Rev., 36, 463-473, doi: 10.1007/s10555-017-9687-8.

238. Slastnikova, T. A., Ulasov, A. V., Rosenkranz, A. A., and Sobolev, A. S. (2018) Targeted intracellular delivery of antibodies: the state of the Art, Front. Pharmacol., 9, 1208, doi: 10.3389/fphar.2018.01208.

239. Ulasov, A. V., Rosenkranz, A. A., and Sobolev, A. S. (2018) Transcription factors: time to deliver, J. Control. Release, 269, 24-35, doi: 10.1016/j.jconrel.2017.11.004.

240. Jin, J. O., Kim, G., Hwang, J., Han, K. H., Kwak, M., and Lee, P. C. W. (2020) Nucleic acid nanotechnology for cancer treatment, Biochim. Biophys. Acta Rev. Cancer, 1874, 188377, doi: 10.1016/j.bbcan.2020.188377.