Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways.
Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways.
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曲妥珠单抗是一种成功的合理设计的ERBB 2靶向治疗。然而，由于各种耐药机制，大约一半的ERBB 2过表达乳腺癌患者对基于曲妥珠单抗的治疗无反应。目前还没有克服不同机制的曲妥珠单抗耐药的临床适用方案。我们发现非受体酪氨酸激酶c-SRC（SRC）是曲妥珠单抗反应的关键调节剂，也是多种曲妥珠单抗耐药途径下游的共同节点。我们发现SRC在获得性和从头曲妥珠单抗耐药细胞中都被激活，并揭示了一种新的SRC调节机制，涉及PTEN的去磷酸化。SRC活化增加赋予乳腺癌细胞相当大的曲妥珠单抗耐药性，并与患者的曲妥珠单抗耐药性相关。靶向SRC联合曲妥珠单抗可使多种曲妥珠单抗耐药细胞系对曲妥珠单抗敏感，并在体内消除曲妥珠单抗耐药肿瘤，表明该策略在克服曲妥珠单抗耐药方面的潜在临床应用。
Trastuzumab is a successful rationally designed ERBB2-targeted therapy. However, about half of individuals with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies, owing to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. We show that the nonreceptor tyrosine kinase c-SRC (SRC) is a key modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. We find that SRC is activated in both acquired and de novo trastuzumab-resistant cells and uncover a novel mechanism of SRC regulation involving dephosphorylation by PTEN. Increased SRC activation conferred considerable trastuzumab resistance in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting SRC in combination with trastuzumab sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.