Journal Article

AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

Taniguchi, Hirokazu, Uchino, Junji, Adachi, Yuta, Yoshimura, Akihiro, Wang, Rong, Watanabe, Satoshi, Matsumoto, Isao, Uehara, Hisanori, Nishiyama, Akihiro, Tanimura, Keiko, Araujo, Luiz H., Kikuchi, Toshiaki, Tanaka, Hiroshi, Miura, Satoru, Shiotsu, Shinsuke, Mukae, Hiroshi, Yamada, Tadaaki, Takeuchi, Shinji, Boroni, Mariana, Yamaguchi, Hiroyuki, Yano, Seiji, Tanimoto, Azusa, Kitazaki, Takeshi, Takayama, Koichi

2019

Overview

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR -mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells. Resistance to the new generation EGFR-TKI, Osimertinib, can emerge in patients with EGFR-mutated lung cancer. Here, the authors show that AXL, which is activated by osimertinib, can promote the emergence of tolerant lung cancer cell thus conferring resistance to osimertinib and propose the combination of Osimertinib with AXL inhibitor as a potential therapeutic approach in such resistant cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/109 / 13/51 / 13/89 / 45/77 / 631/67/1612 / 631/67/1612/1350 / 64/60 / 82/80 / Acrylamides / Adenocarcinoma of Lung - drug therapy / Adenocarcinoma of Lung - genetics / Adenocarcinoma of Lung - pathology / Adult / Aniline Compounds / Animals / Antineoplastic Combined Chemotherapy Protocols - pharmacology / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Axl protein / Cancer / Carcinoma, Non-Small-Cell Lung - drug therapy / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Cell Line, Tumor / Cell survival / Cell Survival - drug effects / Cell Survival - genetics / Disease-Free Survival / Drug Resistance, Neoplasm - genetics / Emergence / Enzyme inhibitors / Epidermal growth factor receptors / ErbB Receptors - antagonists & inhibitors / ErbB Receptors - genetics / ErbB Receptors - metabolism / Feedback loops / Female / Gene Knockdown Techniques / Heterocyclic Compounds, 2-Ring - pharmacology / Heterocyclic Compounds, 2-Ring - therapeutic use / Humanities and Social Sciences / Humans / Inhibitors / Lung - pathology / Lung cancer / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / Male / Mice / Mice, Inbred NOD / multidisciplinary / Mutation / Negative feedback / Neoplasm Recurrence, Local - genetics / Neoplasm Recurrence, Local - pathology / Neoplasm Recurrence, Local - prevention & control / Patients / Piperazines - pharmacology / Piperazines - therapeutic use / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Protein-tyrosine kinase / Proto-Oncogene Proteins - antagonists & inhibitors / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Pyrazoles - pharmacology / Pyrazoles - therapeutic use / Receptor Protein-Tyrosine Kinases - antagonists & inhibitors / Receptor Protein-Tyrosine Kinases - genetics / Receptor Protein-Tyrosine Kinases - metabolism / Receptor, ErbB-3 - genetics / Receptor, ErbB-3 - metabolism / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Targeted cancer therapy / Treatment Outcome / Tumors / Tyrosine / Viability / Xenograft Model Antitumor Assays