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

SummaryEntrectinib is a pan-tyrosine-kinase inhibitor that targets oncogenic rearrangements inNTRK,ROS1 andALK. The combined results of two clinical trials demonstrated the efficacy of entrectinib inROS1-rearranged NSCLC. Because the development of drug resistance is inevitable, it would be helpful to determine the mechanisms of entrectinib resistance in aROS1-rearranged tumor model so that future therapeutic strategies can be developed. Here, we characterized the molecular basis of resistance in entrectinib-resistantROS1-rearranged HCC78 cells (HCC78ER cells). These cells were analyzed by next-generation sequencing and genetic profiling, which revealed the acquisition ofKRAS G12C and the amplification ofKRAS andFGF3. 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 inROS1-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 inROS1-rearranged NSCLC.

Source: Investigational New Drugs - May 23, 2019 Category: Drugs & Pharmacology Source Type: research