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

Hirokazu Taniguchi, Tadaaki Yamada (), Rong Wang, Keiko Tanimura, Yuta Adachi, Akihiro Nishiyama, Azusa Tanimoto, Shinji Takeuchi, Luiz H. Araujo, Mariana Boroni, Akihiro Yoshimura, Shinsuke Shiotsu, Isao Matsumoto, Satoshi Watanabe, Toshiaki Kikuchi, Satoru Miura, Hiroshi Tanaka, Takeshi Kitazaki, Hiroyuki Yamaguchi, Hiroshi Mukae, Junji Uchino, Hisanori Uehara, Koichi Takayama and Seiji Yano ()
Additional contact information
Hirokazu Taniguchi: Kanazawa University
Tadaaki Yamada: Kanazawa University
Rong Wang: Kanazawa University
Keiko Tanimura: Kyoto Prefectural University of Medicine
Yuta Adachi: Kanazawa University
Akihiro Nishiyama: Kanazawa University
Azusa Tanimoto: Kanazawa University
Shinji Takeuchi: Kanazawa University
Luiz H. Araujo: Brazilian National Cancer Institute
Mariana Boroni: Brazilian National Cancer Institute
Akihiro Yoshimura: Kyoto Prefectural University of Medicine
Shinsuke Shiotsu: Japanese Red Cross Kyoto Daiichi Hospital
Isao Matsumoto: Kanazawa University
Satoshi Watanabe: Niigata University Graduate School of Medical and Dental Sciences
Toshiaki Kikuchi: Niigata University Graduate School of Medical and Dental Sciences
Satoru Miura: Niigata Cancer Center Hospital
Hiroshi Tanaka: Niigata Cancer Center Hospital
Takeshi Kitazaki: Japanese Red Cross Nagasaki Genbaku Hospital
Hiroyuki Yamaguchi: Nagasaki University Graduate School of Biomedical Sciences
Hiroshi Mukae: Nagasaki University Graduate School of Biomedical Sciences
Junji Uchino: Kyoto Prefectural University of Medicine
Hisanori Uehara: Tokushima University Graduate School
Koichi Takayama: Kyoto Prefectural University of Medicine
Seiji Yano: Kanazawa University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-08074-0

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