RRC ID 66869
著者 Namba K, Shien K, Takahashi Y, Torigoe H, Sato H, Yoshioka T, Takeda T, Kurihara E, Ogoshi Y, Yamamoto H, Soh J, Tomida S, Toyooka S.
タイトル Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells.
ジャーナル Mol Cancer Res
Abstract Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.
巻・号 17(2)
ページ 499-507
公開日 2019-2-1
DOI 10.1158/1541-7786.MCR-18-0628
PII 1541-7786.MCR-18-0628
PMID 30463991
MeSH Acrylamides / pharmacology* Aniline Compounds / pharmacology* Animals Axl Receptor Tyrosine Kinase Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / enzymology Carcinoma, Non-Small-Cell Lung / genetics* Carcinoma, Non-Small-Cell Lung / pathology Cell Line, Tumor Drug Resistance, Neoplasm Enzyme Activation ErbB Receptors / genetics Female Humans Lung Neoplasms / drug therapy* Lung Neoplasms / enzymology Lung Neoplasms / genetics* Lung Neoplasms / pathology Mice Mice, Inbred BALB C Mice, Nude Mutation Proto-Oncogene Proteins / genetics* Proto-Oncogene Proteins / metabolism Receptor Protein-Tyrosine Kinases / genetics* Receptor Protein-Tyrosine Kinases / metabolism Transfection
IF 4.63
リソース情報
ヒト・動物細胞 PC-9(RCB4455)