Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR -Mutant Non-Small Cell Lung Cancer Cells

• Published in: Molecular cancer research 2019-02, Vol.17 (2), p.499-507
• Main Authors: Namba, Kei, Shien, Kazuhiko, Takahashi, Yuta, Torigoe, Hidejiro, Sato, Hiroki, Yoshioka, Takahiro, Takeda, Tatsuaki, Kurihara, Eisuke, Ogoshi, Yusuke, Yamamoto, Hiromasa, Soh, Junichi, Tomida, Shuta, Toyooka, Shinichi
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Aniline Compounds - pharmacology; Animals; 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
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-0628

Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with -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 -mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from -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 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 -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 and . 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.