Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer

Article metrics


Osimertinib is an irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is highly selective for EGFR-activating mutations as well as the EGFR T790M mutation in patients with advanced non-small cell lung cancer (NSCLC) with EGFR oncogene addiction. Despite the documented efficacy of osimertinib in first- and second-line settings, patients inevitably develop resistance, with no further clear-cut therapeutic options to date other than chemotherapy and locally ablative therapy for selected individuals. On account of the high degree of tumour heterogeneity and adaptive cellular signalling pathways in NSCLC, the acquired osimertinib resistance is highly heterogeneous, encompassing EGFR-dependent as well as EGFR-independent mechanisms. Furthermore, data from repeat plasma genotyping analyses have highlighted differences in the frequency and preponderance of resistance mechanisms when osimertinib is administered in a front-line versus second-line setting, underlying the discrepancies in selection pressure and clonal evolution. This review summarises the molecular mechanisms of resistance to osimertinib in patients with advanced EGFR-mutated NSCLC, including MET/HER2 amplification, activation of the RAS–mitogen-activated protein kinase (MAPK) or RAS–phosphatidylinositol 3-kinase (PI3K) pathways, novel fusion events and histological/phenotypic transformation, as well as discussing the current evidence regarding potential new approaches to counteract osimertinib resistance.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C. et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med 361, 958–967 (2009).

  2. 2.

    Shi, Y., Au, J. S.-K., Thongprasert, S., Srinivasan, S., Tsai, C.-M., Khoa, M. T. et al. A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non–Small-Cell Lung Cancer of Adenocarcinoma Histology (PIONEER). J. Thorac. Oncol. 9, 154–162 (2014).

  3. 3.

    Recondo, G., Facchinetti, F., Olaussen, K. A., Besse, B. & Friboulet, L. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat. Rev. Clin. Oncol. 15, 694–708 (2018).

  4. 4.

    Lim, S. M., Syn, N. L., Cho, B. C. & Soo, R. A. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. Cancer Treat. Rev. 65, 1–10 (2018).

  5. 5.

    Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Disco. 4, 1046–1061 (2014).

  6. 6.

    Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H. et al. Osimertinib in untreated EGFR -mutated advanced non–small-cell lung cancer. N. Engl. J. Med 378, 113–125 (2018).

  7. 7.

    Jänne, P. A., Yang, J. C.-H., Kim, D.-W., Planchard, D., Ohe, Y., Ramalingam, S. S. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med 372, 1689–1699 (2015).

  8. 8.

    Yang, J. C.-H., Ahn, M.-J., Kim, D.-W., Ramalingam, S. S., Sequist, L. V., Su, W.-C. et al. Osimertinib in pretreated T790M-positive advanced non–small-cell lung cancer: AURA study phase II extension component. J. Clin. Oncol. 35, 1288–1296 (2017).

  9. 9.

    Goss, G., Tsai, C. M., Shepherd, F. A., Bazhenova, L., Lee, J. S., Chang, G. C. et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 17, 1643–1652 (2016).

  10. 10.

    Mok, T. S., Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Kim, H. R., Ramalingam, S. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med 376, 629–640 (2017).

  11. 11.

    Ahn, M.-J., Tsai, C.-M., Shepherd, F. A., Bazhenova, L., Sequist, L. V., Hida, T. et al. Osimertinib in patients with T790M mutation‐positive, advanced non–small cell lung cancer: long‐term follow‐up from a pooled analysis of 2 phase 2 studies. Cancer 125, 892–901 (2019).

  12. 12.

    Ramalingam, S. S., Yang, J. C. H., Lee, C. K., Kurata, T., Kim, D.-W., John, T. et al. Osimertinib as first-line treatment of egfr mutation–positive advanced non–small-cell lung cancer. J. Clin. Oncol. 36, 841–849 (2018).

  13. 13.

    Planchard, D., Popat, S., Kerr, K., Novello, S., Smit, E. F., Faivre-Finn, C. et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv192–iv237 (2018).

  14. 14.

    Heon, S., Yeap, B. Y., Britt, G. J., Costa, D. B., Rabin, M. S., Jackman, D. M. et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin. Cancer Res 16, 5873–5882 (2010).

  15. 15.

    Ballard, P., Yates, J. W. T., Yang, Z., Kim, D.-W., Yang, J. C.-H., Cantarini, M. et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. Clin. Cancer Res 22, 5130–5140 (2016).

  16. 16.

    Leonetti, A., Facchinetti, F. & Tiseo, M. Upfront osimertinib in EGFR-mutated non-small cell lung cancer: is brain still a sanctuary? Ann. Transl. Med 6, S110 (2018).

  17. 17.

    Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Han, J.-Y., Katakami, N., Kim, H. R. et al. CNS efficacy of osimertinib in patients with T790M-Positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J. Clin. Oncol. 36, 2702–2709 (2018).

  18. 18.

    Reungwetwattana, T., Nakagawa, K., Cho, B. C., Cobo, M., Cho, E. K., Bertolini, A. et al. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR -mutated advanced non–small-cell lung cancer. J. Clin. Oncol. 36, 3290–3297 (2018).

  19. 19.

    Yang, J. C.-H., Cho, B. C., Kim, D.-W., Kim, S.-W., Lee, J.-S., Su, W.-C. et al. Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study. J. Clin. Oncol. 35, 2020–2020 (2018).

  20. 20.

    Papadimitrakopoulou V. A., Wu Y.-L., Han J.-Y., Ahn M.-J., Ramalingam S. S., John T. et al. LBA51Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study. Ann. Oncol. 29, (2018).

  21. 21.

    Oxnard, G. R., Hu, Y., Mileham, K. F., Husain, H., Costa, D. B., Tracy, P. et al. 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 (2018).

  22. 22.

    Lin, C. C., Shih, J. Y., Yu, C. J., Ho, C. C., Liao, W. Y., Lee, J. H. et al. Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study. Lancet Respir. Med 6, 107–116 (2018).

  23. 23.

    Le, X., Puri, S., Negrao, M. V., Nilsson, M. B., Robichaux, J., Boyle, T. et al. Landscape of EGFR-dependent and -independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC. Clin. Cancer Res 24, 6195–6203 (2018).

  24. 24.

    Zhao, S., Li, X., Zhao, C., Jiang, T., Jia, Y., Shi, J. et al. Loss of T790M mutation is associated with early progression to osimertinib in Chinese patients with advanced NSCLC who are harboring EGFR T790M. Lung Cancer 128, 33–39 (2019).

  25. 25.

    Ramalingam S. S., Cheng Y., Zhou C., Ohe Y., Imamura F., Cho B. C. et al. LBA50Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study. Ann. Oncol. 29 (2018).

  26. 26.

    Yang, Z., Yang, N., Ou, Q., Xiang, Y., Jiang, T., Wu, X. et al. Investigating novel resistance mechanisms to third-generation egfr tyrosine kinase inhibitor osimertinib in non–small cell lung cancer patients. Clin. Cancer Res 24, 3097–3107 (2018).

  27. 27.

    Jiang, T., Su, C., Ren, S., Cappuzzo, F., Rocco, G., Palmer, J. D. et al. A consensus on the role of osimertinib in non-small cell lung cancer from the AME Lung Cancer Collaborative Group. J. Thorac. Dis. 10, 3909–3921 (2018).

  28. 28.

    Niederst, M. J., Hu, H., Mulvey, H. E., Lockerman, E. L., Garcia, A. R., Piotrowska, Z. et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies. Clin. Cancer Res 21, 3924–3933 (2015).

  29. 29.

    Wu, Y. L., Hodge, R., Papadimitrakopoulou, V., He, Y., Mok, T., Delmonte, A. et al. MA08.03 osimertinib vs platinum-pemetrexed for T790M-mutation positive advanced NSCLC (AURA3): plasma ctDNA analysis. J. Thorac. Oncol. 12, S386 (2017).

  30. 30.

    Wang, Z., Yang, J. J., Huang, J., Ye, J. Y., Zhang, X. C., Tu, H. Y. et al. Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance. J. Thorac. Oncol. 12, 1723–1727 (2017).

  31. 31.

    Arulananda, S., Do, H., Musafer, A., Mitchell, P., Dobrovic, A., John, T. Combination osimertinib and gefitinib in C797S and T790M EGFR-mutated non–small cell lung cancer. J. Thorac. Oncol. 12, 1728–1732 (2017).

  32. 32.

    Menon, R., Müller, J., Schneider, P., Lakis, S., Thress, K., Wolf, J. et al. A novel EGFR C797 variant detected in a pleural biopsy specimen from an osimertinib-treated patient using a comprehensive hybrid capture–based next-generation sequencing assay. J. Thorac. Oncol. 11, e105–e107 (2016).

  33. 33.

    Zhang, Q., Zhang, X.-C., Yang, J.-J., Yang, Z.-F., Bai, Y., Su, J. et al. EGFR L792H and G796R: two novel mutations mediating resistance to the third-generation EGFR Tyrosine kinase inhibitor osimertinib. J. Thorac. Oncol. 13, 1415–1421 (2018).

  34. 34.

    Ou, S.-H. I., Cui, J., Schrock, A. B., Goldberg, M. E., Zhu, V. W., Albacker, L. et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer 108, 228–231 (2017).

  35. 35.

    Zheng, D., Hu, M., Bai, Y., Zhu, X., Lu, X., Wu, C. et al. EGFR G796D mutation mediates resistance to osimertinib. Oncotarget 8, 49671–49679 (2017).

  36. 36.

    Bersanelli, M., Minari, R., Bordi, P., Gnetti, L., Bozzetti, C., Squadrilli, A. et al. L718Q mutation as new mechanism of acquired resistance to AZD9291 in EGFR -mutated NSCLC. J. Thorac. Oncol. 11, e121–e123 (2016).

  37. 37.

    Ercan, D., Choi, H. G., Yun, C.-H., Capelletti, M., Xie, T., Eck, M. J. et al. EGFR Mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin. Cancer Res 21, 3913–3923 (2015).

  38. 38.

    Zhang, Y., He, B., Zhou, D., Li, M. & Hu, C. Newly emergent acquired EGFR exon 18 G724S mutation after resistance of a T790M specific EGFR inhibitor osimertinib in non-small-cell lung cancer: a case report. Onco Targets Ther. 12, 51–56 (2018).

  39. 39.

    Fassunke, J., Müller, F., Keul, M., Michels, S., Dammert, M. A., Schmitt, A. et al. Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors. Nat. Commun. 9, 4655 (2018).

  40. 40.

    Peled, N., Roisman, L. C., Miron, B., Pfeffer, R., Lanman, R. B., Ilouze, M. et al. Subclonal therapy by two EGFR TKIs guided by sequential plasma cell-free DNA in EGFR -mutated lung cancer. J. Thorac. Oncol. 12, e81–e84 (2017).

  41. 41.

    Oztan, A., Fischer, S., Schrock, A. B., Erlich, R. L., Lovly, C. M., Stephens, P. J. et al. Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib. Lung Cancer 111, 84–87 (2017).

  42. 42.

    Schoenfeld, A. J., Chan, J. M., Rizvi, H., Rekhtman, N., Daneshbod, Y., Kubota, D. et al. Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR-mutant lung cancers. J. Clin. Oncol. 37, 9028 (2019).

  43. 43.

    Brown, B. P., Zhang, Y.-K., Westover, D., Yan, Y., Qiao, H., Huang, V. et al. On-target resistance to the mutant-selective EGFR Inhibitor osimertinib can develop in an allele-specific manner dependent on the original EGFR-activating mutation. Clin. Cancer Res 25, 3341–3351 (2019).

  44. 44.

    Leventakos, K., Kipp, B. R., Rumilla, K. M., Winters, J. L., Yi, E. S. & Mansfield, A. S. S768I mutation in EGFR in patients with lung cancer. J. Thorac. Oncol. 11, 1798–1801 (2016).

  45. 45.

    Nukaga, S., Yasuda, H., Tsuchihara, K., Hamamoto, J., Masuzawa, K., Kawada, I. et al. Amplification of EGFR wild-type alleles in non–small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res 77, 2078–2089 (2017).

  46. 46.

    Knebel, F. H., Bettoni, F., Shimada, A. K., Cruz, M., Alessi, J. V., Negrão, M. V. et al. Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC. Lung Cancer 108, 238–241 (2017).

  47. 47.

    Shi, Y., Xing, P., Han, X., Wang, S., Liu, Y., Liu, P. et al. P1.13-18 exploring the resistance mechanism of osimertinib and monitoring the treatment response using plasma ctDNA in Chinese NSCLC patients. J. Thorac. Oncol. 13, S589 (2018).

  48. 48.

    Kim, T. M., Song, A., Kim, D.-W., Kim, S., Ahn, Y.-O., Keam, B. et al. Mechanisms of acquired resistance to AZD9291. J. Thorac. Oncol. 10, 1736–1744 (2015).

  49. 49.

    Yu, H. A., Arcila, M. E., Rekhtman, N., Sima, C. S., Zakowski, M. F., Pao, W. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res 19, 2240–2247 (2013).

  50. 50.

    Chabon, J. J., Simmons, A. D., Lovejoy, A. F., Esfahani, M. S., Newman, A. M., Haringsma, H. J. et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat. Commun. 7, 11815 (2016).

  51. 51.

    Shi, P., Oh, Y.-T., Zhang, G., Yao, W., Yue, P., Li, Y. et al. Met gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment. Cancer Lett. 380, 494–504 (2016).

  52. 52.

    Martinez-Marti, A., Felip, E., Matito, J., Mereu, E., Navarro, A., Cedrés, S. et al. Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC). Ann. Oncol. 28, 2451–2457 (2017).

  53. 53.

    O’Kane, G. M., Barnes, T. A. & Leighl, N. B. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors, T790M, and clinical trials. Curr. Oncol. 25, S28–S37 (2018).

  54. 54.

    Ortiz-Cuaran, S., Scheffler, M., Plenker, D., Dahmen, L., Scheel, A. H., Fernandez-Cuesta, L. et al. Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors. Clin. Cancer Res 22, 4837–4847 (2016).

  55. 55.

    Xu C., Wang W., Zhu Y., Yu Z., Zhang H., Wang H. et al. 114OPotential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ non-small cell lung cancer patients with primary resistance to osimertinib: a multicenter study. Ann. Oncol. 30, (2019).

  56. 56.

    York, E. R., Varella-Garcia, M., Bang, T. J., Aisner, D. L. & Camidge, D. R. Tolerable and Effective Combination of Full-Dose Crizotinib and Osimertinib Targeting MET Amplification Sequentially Emerging after T790M Positivity in EGFR- Mutant Non–Small Cell Lung Cancer. J. Thorac. Oncol. 12, e85–e88 (2017).

  57. 57.

    Deng, L., Kiedrowski, L. A., Ravera, E., Cheng, H. & Halmos, B. Response to dual crizotinib and osimertinib treatment in a lung cancer patient with MET amplification detected by liquid biopsy who acquired secondary resistance to EGFR tyrosine kinase inhibition. J. Thorac. Oncol. 13, e169–e172 (2018).

  58. 58.

    Zhu, V. W., Schrock, A. B., Ali, S. M., Ou & S-HI. Differential response to a combination of full-dose osimertinib and crizotinib in a patient with EGFR-mutant non-small cell lung cancer and emergent MET amplification. Lung Cancer Targets Ther. 10, 21–26 (2019).

  59. 59.

    Suzawa, K., Offin, M., Schoenfeld, A. J., Plodkowski, A. J., Odintsov, I., Lu, D. et al. Acquired MET exon 14 alteration drives secondary resistance to epidermal growth factor receptor tyrosine kinase inhibitor in EGFR -mutated lung cancer. JCO Precis Oncol. 3, 1–8 (2019).

  60. 60.

    Planchard, D., Loriot, Y., André, F., Gobert, A., Auger, N., Lacroix, L. et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients. Ann. Oncol. 26, 2073–2078 (2015).

  61. 61.

    Takezawa, K., Pirazzoli, V., Arcila, M. E., Nebhan, C. A., 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 EGFRT790M mutation. Cancer Disco. 2, 922–933 (2012).

  62. 62.

    Eberlein, C. A., Stetson, D., Markovets, A. A., Al-Kadhimi, K. J., Lai, Z., Fisher, P. R. et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res 75, 2489–2500 (2015).

  63. 63.

    Hong M. H., Kim M. H., Kim S.-Y., Heo S. G., Kang H.-N., Park C.-W. et al. 1429PMolecular landscape of osimertinib resistance revealed by targeted panel sequencing and patient-derived cancer models in non-small cell lung cancer patients. Ann. Oncol. 29, (2018).

  64. 64.

    Ho, C.-C., Liao, W.-Y., Lin, C.-A., Shih, J.-Y., Yu, C.-J. & Chih-Hsin Yang, J. Acquired BRAF V600E mutation as resistant mechanism after treatment with osimertinib. J. Thorac. Oncol. 12, 567–572 (2017).

  65. 65.

    Oxnard, G., Thress, K., Paweletz, D., Stetson, D., Dougherty, B., Lai, Z. et al. Mechanisms of acquired resistance to AZD9291 in EGFRT790M positive lung cancer. J. Thorac. Oncol. 10, S173–S260 (2015).

  66. 66.

    Minari, R., Bordi, P., La Monica, S., Squadrilli, A., Leonetti, A., Bottarelli, L. et al. Concurrent acquired BRAF V600E mutation and MET amplification as resistance mechanism of first-line osimertinib treatment in a patient with EGFR-mutated NSCLC. J. Thorac. Oncol. 13, e89–e91 (2018).

  67. 67.

    Barnes, T. A., O’Kane, G. M., Vincent, M. D. & Leighl, N. B. Third-generation tyrosine kinase inhibitors targeting epidermal growth factor receptor mutations in non-small cell lung cancer. Front Oncol. 7, 113 (2017).

  68. 68.

    Eng, J., Woo, K. M., Sima, C. S., Plodkowski, A., Hellmann, M. D., Chaft, J. E. et al. Impact of concurrent PIK3CA mutations on response to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers and on prognosis in oncogene-driven lung adenocarcinomas. J. Thorac. Oncol. 10, 1713–1719 (2015).

  69. 69.

    Gupta, S., Ramjaun, A. R., Haiko, P., Wang, Y., Warne, P. H., Nicke, B. et al. Binding of Ras to phosphoinositide 3-Kinase p110α is required for Ras- driven tumorigenesis in mice. Cell 129, 957–968 (2007).

  70. 70.

    Blakely, C. M., Watkins, T. B. K., Wu, W., Gini, B., Chabon, J. J., McCoach, C. E. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet 49, 1693–1704 (2017).

  71. 71.

    Piotrowska, Z., Isozaki, H., Lennerz, J. K., Gainor, J. F., Lennes, I. T., Zhu, V. W. et al. 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 Disco. 8, 1529–1539 (2018).

  72. 72.

    Zeng, L., Yang, N. & Zhang, Y. GOPC - ROS1 rearrangement as an acquired resistance mechanism to osimertinib and responding to crizotinib combined treatments in lung adenocarcinoma. J. Thorac. Oncol. 13, e114–e116 (2018).

  73. 73.

    Schrock, A. B., Zhu, V. W., Hsieh, W.-S., Madison, R., Creelan, B., Silberberg, J. et al. Receptor tyrosine kinase fusions and BRAF kinase fusions are rare but actionable resistance mechanisms to EGFR tyrosine kinase inhibitors. J. Thorac. Oncol. 13, 1312–1323 (2018).

  74. 74.

    Offin, M., Somwar, R., Rekhtman, N., Benayed, R., Chang, J. C., Plodkowski, A. et al. Acquired ALK and RET gene fusions as mechanisms of resistance to osimertinib in EGFR -mutant lung cancers. JCO Precis Oncol. 2, 1–12 (2018).

  75. 75.

    Minari, R., Bordi, P., Del Re, M., Facchinetti, F., Mazzoni, F., Barbieri, F. et al. Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy. Lung Cancer 115, 21–27 (2018).

  76. 76.

    Li, L., Wang, H., Li, C., Wang, Z., Zhang, P. & Yan, X. Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: a case report. Oncotarget 8, 18609–18614 (2017).

  77. 77.

    Ham, J. S., Kim, S., Kim, H. K., Byeon, S., Sun, J.-M., Lee, S. et al. Two cases of small cell lung cancer transformation from EGFR mutant adenocarcinoma during AZD9291 treatment. J. Thorac. Oncol. 11, e1–e4 (2016).

  78. 78.

    Taniguchi, Y., Horiuchi, H., Morikawa, T. & Usui, K. Small-cell carcinoma transformation of pulmonary adenocarcinoma after osimertinib treatment: a case report. Case Rep. Oncol. 11, 323–329 (2018).

  79. 79.

    Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med 3, 75ra26 (2011).

  80. 80.

    Lee, J.-K., Lee, J., Kim, S., Kim, S., Youk, J., Park, S. et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J. Clin. Oncol. 35, 3065–3074 (2017).

  81. 81.

    Niederst, M. J., Sequist, L. V., Poirier, J. T., Mermel, C. H., Lockerman, E. L., Garcia, A. R. et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6, 6377 (2015).

  82. 82.

    Weng, C.-H., Chen, L.-Y., Lin, Y.-C., Shih, J.-Y., Lin, Y.-C., Tseng, R.-Y. et al. Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI. Oncogene 38, 455–468 (2019).

  83. 83.

    Ichihara, E., Westover, D., Meador, C. B., Yan, Y., Bauer, J. A., Lu, P. et al. SFK/FAK signaling attenuates osimertinib efficacy in both drug-sensitive and drug-resistant models of EGFR-mutant lung cancer. Cancer Res 77, 2990–3000 (2017).

  84. 84.

    Yochum, Z. A., Cades, J., Wang, H., Chatterjee, S., Simons, B. W., O’Brien, J. P. et al. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene 38, 656–670 (2019).

  85. 85.

    Taniguchi, H., Yamada, T., Wang, R., Tanimura, K., Adachi, Y., Nishiyama, A. et al. AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells. Nat. Commun. 10, 259 (2019).

  86. 86.

    Ricordel, C., Friboulet, L., Facchinetti, F. & Soria, J.-C. Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer. Ann. Oncol. 29, i28–i37 (2018).

  87. 87.

    Pakkala, S. & Ramalingam, S. S. Personalized therapy for lung cancer: striking a moving target. JCI Insight 3, 120858 (2018).

  88. 88.

    Engel, J., Richters, A., Getlik, M., Tomassi, S., Keul, M., Termathe, M. et al. Targeting drug resistance in EGFR with covalent inhibitors: a structure-based design approach. J. Med Chem. 58, 6844–6863 (2015).

  89. 89.

    Wang, S., Song, Y. & Liu, D. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance. Cancer Lett. 385, 51–54 (2017).

  90. 90.

    Noda-Narita, S. & Kanda, S. Overcoming resistance to third-generation epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer. Transl. Cancer Res 6, S1187–S1190 (2017).

  91. 91.

    To, C., Jang, J., Chen, T., Park, E., Mushajiang, M., De Clercq, D. J. H. et al. Single and dual targeting of mutant EGFR with an allosteric inhibitor. Cancer Disco. 9, 926–943 (2019).

  92. 92.

    Uchibori, K., Inase, N., Araki, M., Kamada, M., Sato, S., Okuno, Y. et al. Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Nat. Commun. 8, 14768 (2017).

  93. 93.

    Wang, X., Zhou, L., Yin, J. C., Wu, X., Shao, Y. W. & Gao, B. Lung Adenocarcinoma harboring EGFR 19del/C797S/T790M triple mutations responds to brigatinib and Anti-EGFR antibody combination therapy. J. Thorac. Oncol. 14, e85–e88 (2019).

  94. 94.

    Zhao, J., Zou, M., Lv, J., Han, Y., Wang, G. & Wang, G. Effective treatment of pulmonary adenocarcinoma harboring triple EGFR mutations of L858R, T790M, and cis-C797S by osimertinib, bevacizumab, and brigatinib combination therapy: a case report. Onco Targets Ther. 11, 5545–5550 (2018).

  95. 95.

    Liu, Y., Li, Y., Ou, Q., Wu, X., Wang, X., Shao, Y. W. et al. Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib. Lung Cancer 118, 1–5 (2018).

  96. 96.

    La Monica, S., Minari, R., Cretella, D., Flammini, L., Fumarola, C., Bonelli, M. et al. Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC. J. Exp. Clin. Cancer Res 38, 222 (2019).

  97. 97.

    Piotrowska, Z., Liu, S. V., Muzikansky, A., Marcoux, N., Banwait, M., Stevens, S. et al. Safety of osimertinib plus chemotherapy in EGFR-mutant NSCLC. J. Clin. Oncol. 36, e21231–e21231 (2018).

  98. 98.

    Okada, M., Tanaka, K., Asahina, H., Harada, T., Hamai, K., Watanabe, K. et al. Safety analysis of an open label, randomized phase 2 study of osimertinib alone versus osimertinib plus carboplatin-pemetrexed for patients with non–small cell lung cancer (NSCLC) that progressed during prior epidermal growth factor receptor (EGFR) tyrosi. J. Clin. Oncol. 36, e21073–e21073 (2018).

  99. 99.

    Nakamura, A., Inoue, A., Morita, S., Hosomi, Y., Kato, T., Fukuhara, T. et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). J. Clin. Oncol. 36, 9005–9005 (2018).

  100. 100.

    Kang, J., Chen, H.-J., Wang, Z., Liu, J., Li, B., Zhang, T. et al. Osimertinib and cabozantinib combinatorial therapy in an EGFR -mutant lung adenocarcinoma patient with multiple MET secondary-site mutations after resistance to crizotinib. J. Thorac. Oncol. 13, e49–e53 (2018).

  101. 101.

    La Monica, S., Cretella, D., Bonelli, M., Fumarola, C., Cavazzoni, A., Digiacomo, G. et al. Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines. J. Exp. Clin. Cancer Res 36, 174 (2017).

  102. 102.

    Tian, Y., Zhang, Z., Miao, L., Yang, Z., Yang, J, Wang, Y. et al. Anexelekto (AXL) increases resistance to EGFR-TKI and activation of AKT and ERK1/2 in non-small cell lung cancer cells. Oncol Res 24, 295–303 (2016).

  103. 103.

    Wang, L. & Bernards, R. Taking advantage of drug resistance, a new approach in the war on cancer. Front Med 12, 490–495 (2018).

  104. 104.

    Amirouchene-Angelozzi, N., Swanton, C. & Bardelli, A. Tumor evolution as a therapeutic target. Cancer Discov. 7, 805–817 (2017).

  105. 105.

    Leite de Oliveira, R., Wang, L. & Bernards, R. With great power comes great vulnerability. Mol. Cell Oncol. 5, e1509488 (2018).

  106. 106.

    Oxnard, G. R., Thress, K. S., Alden, R. S., Lawrance, R., Paweletz, C. P., Cantarini, M. et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non–small-cell lung cancer. J. Clin. Oncol. 34, 3375–3382 (2016).

  107. 107.

    Murtuza, A., Bulbul, A., Shen, J. P., Keshavarzian, P., Woodward, B. D., Lopez-Diaz, F. J. et al. Novel third-generation EGFR tyrosine kinase inhibitors and strategies to overcome therapeutic resistance in lung cancer. Cancer Res 79, 689–698 (2019).

  108. 108.

    Huang, L.-C., Tam, K.-W., Liu, W.-N., Lin, C.-Y., Hsu, K.-W., Hsieh, W.-S. et al. CRISPR/Cas9 genome editing of epidermal growth factor receptor sufficiently abolished oncogenicity in anaplastic thyroid cancer. Dis. Markers 2018, 1–14 (2018).

  109. 109.

    Tang, H. & Shrager, J. B. CRISPR/Cas-mediated genome editing to treat EGFR-mutant lung cancer: a personalized molecular surgical therapy. EMBO Mol. Med 8, 83–85 (2016).

  110. 110.

    New data on mechanisms of acquired resistance after 1st-line Tagrisso in NSCLC support initiation of ORCHARD trial to explore post-progression treatment options. (2019).

Download references

Author information

A.L., S.S., M.T. and E.G. designed the review; A.L., S.S., R.M., P.P., E.G. and M.T. contributed to the writing of the paper.

Correspondence to Elisa Giovannetti.

Ethics declarations

Competing interests

M.T.: advisory boards and speakers’ fee for Astra-Zeneca. The remaining authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.


Grant by AIRC (Italian Association for Cancer Research) to M.T. (grant IG2017-20074), grant by Fondazione CARIPLO-Regione Lombardia to P.P. (grant 2016-1019), grants by Italian Association for Cancer Research, AIRC/Start-Up grant, and by Fondazione Pisana per la Scienza, to E.G.

Consent to publish

Not applicable.

Data availability

Not applicable.

Additional information

Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark