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Open Access 01-04-2020 | NSCLC | PRECLINICAL STUDIES

Entrectinib resistance mechanisms in ROS1-rearranged non-small cell lung cancer

Authors: Bo Mi Ku, Yeon Hee Bae, Kyoung Young Lee, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn

Published in: Investigational New Drugs | Issue 2/2020

Summary

Entrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements in NTRK, ROS1 and ALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib in ROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in a ROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistant ROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and genetic profiling, which revealed the acquisition of KRAS G12C and the amplification of KRAS and FGF3. However, there were no secondary mutations in the ROS1 kinase domain. We also found that sustained ERK activation was involved in entrectinib resistance, and that combined treatment with selumetinib resensitized HCC78ER cells to entrectinib in cell viability and colony formation assays. Our data suggest that activation of the RAS signaling pathway can cause entrectinib resistance in ROS1-rearranged NSCLC, and is unlikely to be overcome by sequential single agent ROS1-targeting strategies against such tumors. Instead, co-targeting ROS1 and MEK may be an effective strategy for overcoming entrectinib resistance in ROS1-rearranged NSCLC.

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Title: Entrectinib resistance mechanisms in ROS1-rearranged non-small cell lung cancer
Authors: Bo Mi Ku
Yeon Hee Bae
Kyoung Young Lee
Jong-Mu Sun
Se-Hoon Lee
Jin Seok Ahn
Keunchil Park
Myung-Ju Ahn
Publication date: 01-04-2020
Publisher: Springer US
Keywords: NSCLC
NSCLC
Crizotinib
Entrectinib
Published in: Investigational New Drugs / Issue 2/2020
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-019-00795-3

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