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ID 58246
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Takeda, Tatsuaki Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences ORCID
Yamamoto, Hiromasa Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences ORCID Kaken ID publons researchmap
Suzawa, Ken Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Tomida, Shuta Center for Comprehensive Genomic Medicine, Okayama University Hospital Kaken ID researchmap
Miyauchi, Shunsaku Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Araki, Kota Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Nakata, Kentaro Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Miura, Akihiro Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Namba, Kei Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Shien, Kazuhiko Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences ORCID Kaken ID publons researchmap
Soh, Junichi Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Shien, Tadahiko Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences ORCID Kaken ID publons researchmap
Kitamura, Yoshihisa Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences ORCID Kaken ID publons researchmap
Sendo, Toshiaki Department of Clinical Pharmacy, Okayama University Graduate School of Medicine,Dentistry and Pharmaceutical Sciences Kaken ID publons researchmap
Toyooka, Shinichi Department of General Thoracic Surgery and Breast and Endocrinological Surgery,Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences ORCID Kaken ID publons researchmap
Abstract
Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.
Keywords
breast cancer
drug resistance
lung cancer
neratinib
YES1
Published Date
2019-12-19
Publication Title
Cancer Science
Volume
volume111
Issue
issue3
Publisher
Wiley
Start Page
849
End Page
856
ISSN
1347-9032
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© 2019 The Authors.
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publisher
PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1111/cas.14289
License
https://creativecommons.org/licenses/by-nc/4.0/
Funder Name
Japan Society for the Promotion of Science
助成番号
19H00408
19K09070