背景:HER2靶向疗法彻底改变了HER2阳性乳腺癌的治疗方法。然而,从头耐药或获得性耐药的出现是一个持续的临床问题。在这里,我们报道了neratinib,一种不可逆的泛HER抑制剂,与多激酶抑制剂达沙替尼联合使用,目前用于治疗某些白血病,对HER2阳性乳腺癌模型具有很强的抗增殖作用,这些乳腺癌固有地对曲妥珠单抗耐药或对neratinib具有获得性耐药。
方法:在一组20个乳腺癌细胞系中检查了Neratinib联合达沙替尼,包括HER2阳性,雌激素受体阳性,三负,和获得性HER2靶向治疗耐药模型。评估药物对迁移和凋亡诱导的作用,并通过反相蛋白质阵列(RPPA)确定信号传导改变。使用原位植入的HCC1954细胞检查体内功效。
结果:在固有的对曲妥珠单抗耐药的细胞系中观察到协同作用,对neratinib具有获得性抗性的模型,和三阴性乳腺癌细胞系。进一步的研究表明,neratinib+dasatinib诱导细胞凋亡并抑制细胞迁移的程度高于单独使用任何一种药物。RPPA显示,该组合通过EGFR抑制了关键生存信号,Akt,和MAPK抑制。在体内,neratinib+dasatinib对HCC1954异种移植瘤的耐受性良好,且具有延长的抗肿瘤作用.
结论:这项研究为neratinib和dasatinib在HER2+乳腺癌中的临床研究提供了强有力的临床前理论基础。
BACKGROUND: HER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib.
METHODS: Neratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells.
RESULTS: Synergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts.
CONCLUSIONS: This study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.