YES1 activation induces acquired resistance to neratinib in HER2 ‐amplified breast and lung cancers
YES1 activation induces acquired resistance to neratinib in HER2 ‐amplified breast and lung cancers
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YES1 激活诱导 HER2 扩增的乳腺癌和肺癌对来那替尼获得性耐药
DOI：
10.1111/cas.14289
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发表时间：
2020
期刊：
影响因子：
5.7
通讯作者：
Toyooka Shinichi
中科院分区：
文献类型：
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作者：
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
针对人表皮生长因子受体2（HER2）的分子靶向疗法正在发展用于各种癌症。来那替尼是一种不可逆的泛HER酪氨酸激酶抑制剂，已被FDA批准为治疗HER2阳性乳腺癌的有效药物。然而，各种癌症对分子靶向药物的获得性耐药性是一个临床问题，对来那替尼的耐药性也被认为是不可避免的。在本研究中，我们使用几种药物暴露条件，从HER2扩增的乳腺癌和肺癌细胞系中建立了各种类型的来那替尼耐药细胞系。我们分析了这些细胞株耐药性产生的机制，并探讨了克服耐药性的有效策略。我们的结果显示，SRC家族成员YES 1的扩增在两种耐来那替尼乳腺癌细胞系和一种肺癌细胞系中扩增。通过siRNA敲低YES 1和达沙替尼对YES 1的药理学抑制恢复了YES 1扩增细胞系对Neratinib的体外敏感性。达沙替尼和来那替尼联合治疗可抑制体内肿瘤生长。这种组合还诱导了信号分子如HER2、AKT和MAPK的下调。我们目前的结果表明，YES 1在HER2靶向药物耐药性的出现中起着重要作用，而达沙替尼能够克服这种获得性耐药性。
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 fromHER2‐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 ofYES1, which is a member of theSRCfamily, was amplified in two neratinib‐resistant breast cancer cell lines and one lung cancer cell line. Knockdown ofYES1by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of theYES1‐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 thatYES1plays an important role in the emergence of resistance to HER2‐targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.