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

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

doi:10.1007/s10637-019-00795-3

Bo Mi Ku, Myung-Ju Ahn + Show 6 more

Open Access

https://doi.org/10.1007/s10637-019-00795-3

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Abstract

SummaryEntrectinib 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.

Highlights

The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the therapeutic targeting of oncogenic mutations, and tyrosine kinase inhibitors (TKIs) have emerged as a successful treatment modality [1,2,3]
Activation of EGFR or c-MET signaling has been reported in HCC78 cells suggesting inhibition of ROS1 pathway only might not be effective in vitro model system [19,20,21]
To evaluate whether the parental HCC78 cells are dependent upon other receptor tyrosine kinase such as EGFR or c-MET, we conducted proteome profiler array using the Human XL Oncology Array Kit

Summary

Introduction

The treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the therapeutic targeting of oncogenic mutations, and tyrosine kinase inhibitors (TKIs) have emerged as a successful treatment modality [1,2,3]. The present challenge in TKI-based targeted therapy is to identify. ROS1 gene rearrangements occur in ~1–2% of patients with NSCLC, and have been identified in colorectal, gastric and ovarian cancers, glioblastoma and cholangiocarcinoma [4,5,6,7]. ROS1-rearranged NSCLCs are ‘addicted’ to ROS1 for cell growth and survival. Knocking down or pharmacologically inhibiting ROS1 has been reported to inhibit growth or induce apoptosis in ROS1-rearranged cell lines [5]

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