Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Mechanisms of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance and Strategies to Overcome Resistance in Lung Adenocarcinoma

  • Chang, Yoon Soo (Department of Internal Medicine, Yonsei University College of Medicine) ;
  • Choi, Chang-Min (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Lee, Jae Cheol (Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2016.06.27
  • Accepted : 2016.08.25
  • Published : 2016.10.05
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Abstract

Somatic mutations that lead to hyperactivation of epidermal growth factor receptor (EGFR) signaling are detected in approximately 50% of lung adenocarcinoma in people from the Far East population and tyrosine kinase inhibitors are now the standard first line treatment for advanced disease. They have led to a doubling of progression-free survival and an increase in overall survival by more than 2 years. However, emergence of resistant clones has become the primary cause for treatment failure, and has created a new challenge in the daily management of patients with EGFR mutations. Identification of mechanisms leading to inhibitor resistance has led to new therapeutic modalities, some of which have now been adapted for patients with unsuccessful tyrosine kinase inhibitor treatment. In this review, we describe mechanisms of tyrosine kinase inhibitor resistance and the available strategies to overcoming resistance.

Keywords

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin 2015;65:87-108. https://doi.org/10.3322/caac.21262
  2. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 2004;59(2 Suppl):21-6. https://doi.org/10.1016/j.ijrobp.2003.10.027
  3. Yarden Y, Schlessinger J. Epidermal growth factor induces rapid, reversible aggregation of the purified epidermal growth factor receptor. Biochemistry 1987;26:1443-51. https://doi.org/10.1021/bi00379a035
  4. Downward J, Parker P, Waterfield MD. Autophosphorylation sites on the epidermal growth factor receptor. Nature 1984;311:483-5. https://doi.org/10.1038/311483a0
  5. Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol 2005;1:2005.0010.
  6. Walker F, Abramowitz L, Benabderrahmane D, Duval X, Descatoire V, Henin D, et al. Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus. Hum Pathol 2009;40:1517-27. https://doi.org/10.1016/j.humpath.2009.05.010
  7. Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 2001;8:83-96. https://doi.org/10.1677/erc.0.0080083
  8. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39. https://doi.org/10.1056/NEJMoa040938
  9. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. https://doi.org/10.1056/NEJMoa0810699
  10. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for nonsmall-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. https://doi.org/10.1056/NEJMoa0909530
  11. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. https://doi.org/10.1016/S1470-2045(09)70364-X
  12. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. https://doi.org/10.1016/S1470-2045(11)70393-X
  13. Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42. https://doi.org/10.1016/S1470-2045(11)70184-X
  14. Zhou C, Yao LD. Strategies to improve outcomes of patients with EGRF-mutant non-small cell lung cancer: review of the literature. J Thorac Oncol 2016;11:174-86. https://doi.org/10.1016/j.jtho.2015.10.002
  15. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [corrected]. J Clin Oncol 2003;21:2237-46. https://doi.org/10.1200/JCO.2003.10.038
  16. Thatcher N, Chang A, Parikh P, Rodrigues Pereira J, Ciuleanu T, von Pawel J, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced nonsmall- cell lung cancer: results from a randomised, placebocontrolled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527-37. https://doi.org/10.1016/S0140-6736(05)67625-8
  17. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004;101:13306-11. https://doi.org/10.1073/pnas.0405220101
  18. Inoue A, Kobayashi K, Usui K, Maemondo M, Okinaga S, Mikami I, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol 2009;27:1394-400. https://doi.org/10.1200/JCO.2008.18.7658
  19. Sequist LV, Martins RG, Spigel D, Grunberg SM, Spira A, Janne PA, et al. First-line gefitinib in patients with advanced nonsmall- cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442-9. https://doi.org/10.1200/JCO.2007.14.8494
  20. Yu HA, Riely GJ. Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in lung cancers. J Natl Compr Canc Netw 2013;11:161-9. https://doi.org/10.6004/jnccn.2013.0024
  21. Kim HS, Sung JS, Yang SJ, Kwon NJ, Jin L, Kim ST, et al. Predictive efficacy of low burden EGFR mutation detected by next-generation sequencing on response to EGFR tyrosine kinase inhibitors in non-small-cell lung carcinoma. PLoS One 2013;8:e81975. https://doi.org/10.1371/journal.pone.0081975
  22. Kim EY, Cho EN, Park HS, Hong JY, Lim S, Youn JP, et al. Compound EGFR mutation is frequently detected with comutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma. Cancer Biol Ther 2016;17:237-45. https://doi.org/10.1080/15384047.2016.1139235
  23. Shigematsu H, Lin L, Takahashi T, Nomura M, Suzuki M, Wistuba II, et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-46. https://doi.org/10.1093/jnci/dji055
  24. Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol 2007;25:587-95. https://doi.org/10.1200/JCO.2006.07.3585
  25. Tokumo M, Toyooka S, Kiura K, Shigematsu H, Tomii K, Aoe M, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in nonsmall cell lung cancers. Clin Cancer Res 2005;11:1167-73.
  26. Mitsudomi T, Yatabe Y. Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J 2010;277:301-8. https://doi.org/10.1111/j.1742-4658.2009.07448.x
  27. Mitsudomi T, Yatabe Y. Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer. Cancer Sci 2007;98:1817-24. https://doi.org/10.1111/j.1349-7006.2007.00607.x
  28. Yeh P, Chen H, Andrews J, Naser R, Pao W, Horn L. DNA-mutation Inventory to Refine and Enhance Cancer Treatment (DIRECT): a catalog of clinically relevant cancer mutations to enable genome-directed anticancer therapy. Clin Cancer Res 2013;19:1894-901. https://doi.org/10.1158/1078-0432.CCR-12-1894
  29. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR -mutant non-small-cell lung cancer. Nat Rev Cancer 2010;10:760-74. https://doi.org/10.1038/nrc2947
  30. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012;13:e23-31. https://doi.org/10.1016/S1470-2045(11)70129-2
  31. Yasuda H, Park E, Yun CH, Sng NJ, Lucena-Araujo AR, Yeo WL, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR ) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5:216ra177. https://doi.org/10.1126/scitranslmed.3007205
  32. Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26.
  33. Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med 2012;18:521-8. https://doi.org/10.1038/nm.2713
  34. Cho EN, Kim EY, Jung JY, Kim A, Oh IJ, Kim YC, et al. BCL2-like 11 intron 2 deletion polymorphism is not associated with non-small cell lung cancer risk and prognosis. Lung Cancer 2015;90:106-10. https://doi.org/10.1016/j.lungcan.2015.07.017
  35. Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res 2011;17:3812-21. https://doi.org/10.1158/1078-0432.CCR-10-3408
  36. Kobayashi S, Canepa HM, Bailey AS, Nakayama S, Yamaguchi N, Goldstein MA, et al. Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors. J Thorac Oncol 2013;8:45-51. https://doi.org/10.1097/JTO.0b013e318274a83e
  37. Peng L, Song Z, Jiao S. Comparison of uncommon EGFR exon 21 L858R compound mutations with single mutation. Onco Targets Ther 2015;8:905-10.
  38. Won JK, Keam B, Koh J, Cho HJ, Jeon YK, Kim TM, et al. Concomitant ALK translocation and EGFR mutation in lung cancer: a comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor. Ann Oncol 2015;26:348-54. https://doi.org/10.1093/annonc/mdu530
  39. Wang L, Hu H, Pan Y, Wang R, Li Y, Shen L, et al. PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. PLoS One 2014;9:e88291. https://doi.org/10.1371/journal.pone.0088291
  40. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of nonsmall-cell lung cancer to gefitinib. N Engl J Med 2005;352:786-92. https://doi.org/10.1056/NEJMoa044238
  41. Balak MN, Gong Y, Riely GJ, Somwar R, Li AR, Zakowski MF, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006;12:6494-501. https://doi.org/10.1158/1078-0432.CCR-06-1570
  42. Su KY, Chen HY, Li KC, Kuo ML, Yang JC, Chan WK, et al. Pretreatment epidermal growth factor receptor (EGFR ) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 2012;30:433-40.
  43. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876-80. https://doi.org/10.1126/science.1062538
  44. Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2002;2:117-25. https://doi.org/10.1016/S1535-6108(02)00096-X
  45. O'Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005;65:4500-5. https://doi.org/10.1158/0008-5472.CAN-05-0259
  46. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, et al. Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 2013;3:1404-15. https://doi.org/10.1158/2159-8290.CD-13-0314
  47. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43. https://doi.org/10.1126/science.1141478
  48. Spigel DR, Ervin TJ, Ramlau RA, Daniel DB, Goldschmidt JH Jr, Blumenschein GR Jr, et al. Randomized phase II trial of Onartuzumab in combination with erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol 2013;31:4105-14. https://doi.org/10.1200/JCO.2012.47.4189
  49. Mok TS, Park K, Geater SL, Agarwal S, Han M, Komarnitsky P, et al. A randomized phase 2 study with exploratory biomarker analysis of ficlatuzumab a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antivody, in combination with gefitinib verus gefitinib in Asian patients with lung adenocarcinoma. Ann Oncol 2012;23(Suppl 9):1198P. https://doi.org/10.1093/annonc/mdr404
  50. Feng Y, Thiagarajan PS, Ma PC. MET signaling: novel targeted inhibition and its clinical development in lung cancer. J Thorac Oncol 2012;7:459-67. https://doi.org/10.1097/JTO.0b013e3182417e44
  51. Takezawa K, Pirazzoli V, Arcila ME, Nebhan CA, Song X, de Stanchina E, et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR - mutant lung cancers that lack the second-site EGFR T790M mutation. Cancer Discov 2012;2:922-33. https://doi.org/10.1158/2159-8290.CD-12-0108
  52. Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, et al. LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol 2013;31:3335-41. https://doi.org/10.1200/JCO.2012.45.0981
  53. Regales L, Gong Y, Shen R, de Stanchina E, Vivanco I, Goel A, et al. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 2009;119:3000-10.
  54. Janjigian YY, Smit EF, Groen HJ, Horn L, Gettinger S, Camidge DR, et al. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR -mutant lung cancer with and without T790M mutations. Cancer Discov 2014;4:1036-45. https://doi.org/10.1158/2159-8290.CD-14-0326
  55. Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, et al. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res 2009;69:6871-8. https://doi.org/10.1158/0008-5472.CAN-08-4490
  56. Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Croce K, et al. A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 2007;26:3909-19. https://doi.org/10.1038/sj.onc.1210173
  57. Ohashi K, Sequist LV, Arcila ME, Moran T, Chmielecki J, Lin YL, et al. Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS , or MEK1. Proc Natl Acad Sci U S A 2012;109:E2127-33. https://doi.org/10.1073/pnas.1203530109
  58. Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 2008;100:35-83.
  59. Hafizi S, Dahlback B. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine Growth Factor Rev 2006;17:295-304. https://doi.org/10.1016/j.cytogfr.2006.04.004
  60. Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, et al. Activation of the AXL kinase causes resistance to EGFRtargeted therapy in lung cancer. Nat Genet 2012;44:852-60. https://doi.org/10.1038/ng.2330
  61. Rho JK, Choi YJ, Kim SY, Kim TW, Choi EK, Yoon SJ, et al. MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. Cancer Res 2014;74:253-62.

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