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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2016, Vol. 10 Issue (4) : 383-388     DOI: 10.1007/s11684-016-0488-1
Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors
Shuhang Wang1,Yongping Song2,Feifei Yan1,Delong Liu2()
1. The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital, Beijing 100142, China
2. Henan Cancer Hospital and the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China
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The tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the first line of therapy for advanced non-small cell lung cancer (NSCLC). Acquired mutations in EGFR account for one of the major mechanisms of resistance to the TKIs. Three generations of EGFR TKIs have been used in clinical applications. AZD9291 (osimertinib; Tagrisso) is the first and only FDA approved third-generation EGFR TKI for T790M-positive advanced NSCLC patients. However, resistance to AZD9291 arises after 9–13 months of therapy. The mechanisms of resistance to third-generation inhibitors reported to date include the EGFR C797S mutation, EGFR L718Q mutation, and amplifications of HER-2, MET, or ERBB2. To overcome the acquired resistance to AZD9291, EAI045 was discovered and recently reported to be an allosteric EGFR inhibitor that overcomes T790M- and C797S-mediated resistance. This review summarizes recent investigations on the mechanisms of resistance to the EGFR TKIs, as well as the latest development of EAI045 as a fourth-generation EGFR inhibitor.

Keywords EGFR      tyrosine kinase inhibitor      AZD9291      EAI045     
Corresponding Authors: Delong Liu   
Just Accepted Date: 08 October 2016   Online First Date: 24 October 2016    Issue Date: 01 December 2016
URL:     OR
Case report Pretreatment EGFR mutations Prior treatments Third generation EGFR TKI Gene status at resistance Reference
60 YF del.19 Chemo, erlotinib
Radiotherapy, afatinib/cetuximab
PFS= 9 months
del.19 and T790M and C797S and TSC2N486I [25]
57 YF del.19 Gefitinib, chemo
PFS= 17 months
del.19 and T790M and C797S [27]
71 YF L858R Gefitinib AZD9291
PFS= 13 months
L858R and T790M and L718Q [29]
71 YF del.19 Chemo, erlotinib CO-1686 del.19 and T790M and HER2 A [30]
64 YF L861Q and T790M and HER2 A NA AZD 9291
PFS= 7 months
EGFR L861Q and T790M [30]
54 YF del.19 and T790M and MET amp Chemo, erlotinib CO-1686
PFS= 3 months
NA [30]
57 YM L858R and T790M Gefitinib, chemo AZD9291
PFS= 4 months
EGFR L858R and T790M and MET amp [30]
60 YM del.19 and T790M Erlotinib, chemo
PFS= 18 months
del.19 and T790M and MET amp and HER2 A [30]
56 YF del.19 and T790M Gefitinib, radiotherapy
Erlotinib, afatinib, afatinib/cetuximab
PFS= 22 months
del.19 and T790M and C797S and MET amp [30]
51 YF del.19 and T790M Gefitinib, chemo
Afatinib, afatinib/cetuximab
PFS= 9 months
del.19 and KRAS G12S [30]
Tab.1  Patients with NSCLC who developed resistance to third-generation EGFR TKIs
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