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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-01-16

AUTHORS

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, Seiji Yano

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. More... »

PAGES

259

Journal

TITLE

Nature Communications

ISSUE

1

VOLUME

10

Author Affiliations

  • Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, 852-8501, Nagasaki, Japan
  • Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465, Kajii-cho, Kamigyo-ku, 602-8566, Kyoto, Japan
  • Division of Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1, Takara-machi, 920-0934, Kanazawa, Japan
  • Division of Clinical Research, Brazilian National Cancer Institute, Rua André Cavalcanti 37, 20231-050, Rio de Janeiro − RJ, Brazil
  • Division of Experimental and Translational Research, Bioinformatics and Computational Biology Lab, Brazilian National Cancer Institute, Rua André Cavalcanti 37, 20231-050, Rio de Janeiro − RJ, Brazil
  • Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, 15-749 Hon-machi, Higashiyama-ku, 605-0981, Kyoto, Japan
  • Department of Thoracic, Cardiovascular and General Surgery, Kanazawa University, 13-1, Takara-machi, 920-0934, Kanazawa, Japan
  • Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 1–757 Asahimachi-dori, Chuo-ku, 951-8510, Niigata, Japan
  • Department of Internal Medicine, Niigata Cancer Center Hospital, 2-15-3 Kawagishi-cho, 961-8566, Niigata, Japan
  • Department of Respiratory Medicine, Japanese Red Cross Nagasaki Genbaku Hospital, 3-15 Mori-machi, 852-8511, Nagasaki, Japan
  • Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15, Kuramoto-cho, 770-8503, Tokushima, Japan
  • Nano Life Science Institute, Kanazawa University, Kakuma, 920-1192, Kanazawa, Japan
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-08074-0

    DOI

    http://dx.doi.org/10.1038/s41467-018-08074-0

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111348232

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30651547


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