Mechanisms of resistance to third-generation EGFR tyrosine kinase inhibitors

Abstract

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

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Acknowledgements

This project was partially supported by the National Natural Science Foundation of China (No. 81101726). Shuhang Wang was a recipient of the CAHON Young Investigator Award (www.cahon.org).

Compliance with ethics guideline

Shuhang Wang, Yongping Song, Feifei Yan, and Delong Liu declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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2016 Higher Education Press and Springer-Verlag Berlin Heidelberg