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

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...

Full description

Saved in:
Bibliographic Details
Published in:Investigational new drugs 2020-04, Vol.38 (2), p.360-368
Main Authors: Ku, Bo Mi, Bae, Yeon Hee, Lee, Kyoung Young, Sun, Jong-Mu, Lee, Se-Hoon, Ahn, Jin Seok, Park, Keunchil, Ahn, Myung-Ju
Format: Article
Language:English
Subjects:
Activation
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Benzamides - pharmacology
Benzimidazoles - pharmacology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Cell viability
Clinical trials
Combined treatment
Drug resistance
Drug Resistance, Neoplasm - genetics
Enzyme inhibitors
Extracellular signal-regulated kinase
Fibroblast growth factor 3
Gene Rearrangement
Gene sequencing
Humans
Indazoles - pharmacology
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Medical research
Medicine
Medicine & Public Health
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mutation
Next-generation sequencing
Non-small cell lung carcinoma
Oncology
Pharmacology/Toxicology
Preclinical Studies
Protein Kinase Inhibitors - pharmacology
Protein-Tyrosine Kinases - genetics
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins p21(ras) - genetics
Signal transduction
Tumors
Tyrosine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-019-00795-3