YES1 activation induces acquired resistance to neratinib in HER2‐amplified breast and lung cancers

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 resi...

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Bibliographic Details
Published in:Cancer science 2020-03, Vol.111 (3), p.849-856
Main Authors: Takeda, Tatsuaki, Yamamoto, Hiromasa, Suzawa, Ken, Tomida, Shuta, Miyauchi, Shunsaku, Araki, Kota, Nakata, Kentaro, Miura, Akihiro, Namba, Kei, Shien, Kazuhiko, Soh, Junichi, Shien, Tadahiko, Kitamura, Yoshihisa, Sendo, Toshiaki, Toyooka, Shinichi
Format: Article
Language:English
Subjects:
AKT protein
Animals
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - genetics
Cancer therapies
Cell growth
Cell Line, Tumor
Cell Proliferation - genetics
Deoxyribonucleic acid
DNA
Down-Regulation - genetics
Drug dosages
Drug resistance
Drug Resistance, Neoplasm - genetics
Enzyme inhibitors
Epidermal growth factor
ErbB-2 protein
Female
Gene expression
Humans
Kinases
Laboratories
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
MAP kinase
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Targeted Therapy - methods
neratinib
Original
Protein-tyrosine kinase
Proteins
Proto-Oncogene Proteins c-yes - genetics
Quinolines - pharmacology
Receptor, ErbB-2 - genetics
Signal Transduction - genetics
siRNA
Tumor cell lines
Xenograft Model Antitumor Assays - methods
YES1
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Summary: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. We found that YES1 played an important role in the emergence of resistance to neratinib. The combination therapy of dasatinib, which is a YES1 inhibitor, plus neratinib enabled the resistance to neratinib to be overcome.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14289