Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer.
Combining Neratinib with CDK4/6, mTOR, and MEK Inhibitors in Models of HER2-positive Cancer.
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DOI：
10.1158/1078-0432.ccr-20-3017
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发表时间：
2021-03-15
期刊：
影响因子：
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通讯作者：
Meric-Bernstam F
中科院分区：
文献类型：
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作者：
Zhao M;Scott S;Evans KW;Yuca E;Saridogan T;Zheng X;Wang H;Korkut A;Cruz Pico CX;Demirhan M;Kirby B;Kopetz S;Diala I;Lalani AS;Piha-Paul S;Meric-Bernstam F
Neratinib是一种不可逆转的泛Her酪氨酸激酶抑制剂，FDA批准用于HER2过度表达/放大(HER2+)的乳腺癌。在这项临床前研究中，我们探讨了在体内和体外，奈拉替尼联合下游信号转导抑制剂对HER2+癌症的疗效。采用细胞存活率、集落形成实验和Western blotting等方法检测药物对细胞的影响。体内疗效通过患者来源的异种移植(PDX)进行评估：两例乳腺癌、两例结直肠癌和一例食道癌；两例HER2突变。四个PDX来自以前接受HER2靶向治疗的患者。蛋白质组学通过反相蛋白质阵列(RPPA)进行评估，网络水平适应性反应通过Target Score算法进行评估。在HER2+乳腺癌细胞中，Neratinib与多种药物有协同作用，包括mTOR抑制剂伊维莫司和沙尼司替布、MEK抑制剂曲美替尼、CDK4/6抑制剂Palbociclib和PI3Kα抑制剂Alpelisib。我们在5个HER2+PDX中测试了neratinib与evolimus、trametinib或palbociclib的疗效。在25%(1/4)和60%(3/5)的模型中，neratinib联合依维莫司或曲美替尼可使中位无事件生存期(EFS)增加100%；在所有5个模型中，neratinib与palbociclib联用均可增加EFS。适应性反应的网络分析表明，CDK4/6、mTOR和MEK抑制后，EGFR和HER2信号上调，这可能为观察到与neratinib的协同作用提供了解释。综上所述，我们的研究结果为奈拉替尼联合CDK4/6、mTOR和MEK抑制剂治疗HER2+癌症提供了强有力的临床前证据。Neratinib是一种不可逆转的泛Her酪氨酸激酶抑制剂，FDA批准用于HER2过度表达/放大(HER2+)乳腺癌的佐剂和转移环境。这项临床前研究探索了奈拉替尼的联合治疗。体外HER2扩增结果显示，橙花替尼与mTOR抑制剂维罗莫司和沙巴尼司替布、CDK4/6抑制剂palbociclib、MEK抑制剂曲美替尼和PI3Kα抑制剂alpelisib有协同作用。HER2扩增的肿瘤PDX的体内肿瘤生长研究进一步证实了neratinib与依维莫司、曲美替尼或帕博西利联合使用时的增强治疗效果。RPPA分析和网络水平的适应性反应分析揭示了观察到的与neratinib协同作用的潜在分子机制。综上所述，这项临床前研究的有希望的结果为奈拉替尼与一些通路抑制剂的联合应用提供了强有力的理由。
Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA-approved for HER2-overexpressing/amplified (HER2+) breast cancer. In this preclinical study, we explored the efficacy of neratinib in combination with inhibitors of downstream signaling in HER2+ cancers in vitro and in vivo. Cell viability, colony formation assays, and western blotting were used to determine effect of neratinib in vitro. In vivo efficacy was assessed with patient-derived xenografts (PDXs): two breast, two colorectal and one esophageal cancer; two with HER2 mutations. Four PDXs were derived from patients who received previous HER2-targeted therapy. Proteomics were assessed through Reverse Phase Protein Arrays (RPPA) and network level adaptive responses were assessed through Target Score algorithm. In HER2+ breast cancer cells, neratinib was synergistic with multiple agents, including mTOR inhibitors everolimus and sapanisertib, MEK inhibitor trametinib, CDK4/6 inhibitor palbociclib, and PI3Kα inhibitor alpelisib. We tested efficacy of neratinib with everolimus, trametinib, or palbociclib in five HER2+ PDXs. Neratinib combined with everolimus or trametinib led to a 100% increase in median event-free survival (EFS; tumor doubling time) in 25% (1 of 4) and 60% (3 of 5) models respectively while neratinib with palbociclib increased EFS in all five models. Network analysis of adaptive responses demonstrated upregulation of EGFR and HER2 signaling in response to CDK4/6, mTOR and MEK inhibition, possibly providing an explanation for the observed synergies with neratinib. Taken together, our results provide strong preclinical evidence for combining neratinib with CDK4/6, mTOR and MEK inhibitors for the treatment of HER2+ cancer. Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor that is FDA-approved for HER2-overexpressing/amplified (HER2+) breast cancer in the adjuvant and metastatic setting. This preclinical study explored the combinatorial therapies of neratinib. Results from our in vitro HER2 amplified cell lines showed that neratinib was synergistic with the mTOR inhibitors everolimus and sapanisertib, CDK4/6 inhibitor palbociclib MEK inhibitor trametinib, and PI3Kα inhibitor alpelisib. In vivo tumor growth study of HER2 amplified tumor PDXs further confirmed the enhanced therapeutic efficacy when neratinib was combined with everolimus, trametinib, or palbociclib. RPPA assay and network-level adaptive response analysis revealed potential molecular mechanisms for the observed synergies with neratinib. Taken together, the promising outcomes of this preclinical study provide strong rationale for combining neratinib with a number of pathway inhibitors.