MET抑制剂INC-280联合或不联合表皮生长因子受体抑制剂厄洛替尼用于非小细胞肺癌的临床前评估
Preclinical Evaluation of MET Inhibitor INC-280 With or Without the Epidermal Growth Factor Receptor Inhibitor Erlotinib in Non-Small-Cell Lung Cancer.
作者信息
Lara Matthew S, Holland William S, Chinn Danielle, Burich Rebekah A, Lara Primo N, Gandara David R, Kelly Karen, Mack Philip C
机构信息
Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Davis, CA.
出版信息
Clin Lung Cancer. 2017 May;18(3):281-285. doi: 10.1016/j.cllc.2016.11.006. Epub 2016 Nov 21.
BACKGROUND
Although the epidermal growth factor receptor (EGFR) inhibitor erlotinib is initially effective in non-small-cell lung cancer (NSCLC) patients with tumors harboring activating mutations of EGFR, most subsequently develop acquired resistance. One recognized resistance mechanism occurs through activation of bypass signaling via the hepatocyte growth factor (HGF)-MET pathway. INC-280 is a small molecule kinase inhibitor of MET. We sought to demonstrate the activity of INC-280 on select NSCLC cell lines both as a single agent and in combination with erlotinib using exogenous HGF to simulate MET up-regulation.
METHODS
Four NSCLC cell lines (HCC827, PC9, H1666, and H358) were treated with either single-agent INC-280 or in combination with erlotinib with or without HGF. The activity of the drug treatments was measured by cell viability assays. Immunoblotting was used to monitor expression of EGFR/pEGFR, MET/pMET, GAB1/pGAB1, AKT/pAKT, and ERK/pERK as well as markers of apoptosis (PARP and capase-3 cleavage) in H1666, HCC827, and PC9.
RESULTS
As a single agent, INC-280 showed minimal cytotoxicity despite potent inhibition of MET kinase activity at concentrations as low as 10 nM. Addition of HGF prevented erlotinib-induced cell death. The addition of INC280 to HGF-mediated erlotinib-resistant models restored erlotinib sensitivity for all cell lines tested, associated with cleavage of both PARP and caspase-3. In these models, INC-280 treatment was sufficient to restore erlotinib-induced inhibition of MET, GAB1, AKT, and ERK in the presence of HGF.
CONCLUSION
Although the MET inhibitor INC-280 alone had no discernible effect on cell growth, it was able to restore sensitivity to erlotinib and promote apoptosis in NSCLC models rendered erlotinib resistant by HGF. These data provide a preclinical rationale for an ongoing phase 1 clinical trial of erlotinib plus INC-280 in EGFR-mutated NSCLC.
背景
尽管表皮生长因子受体（EGFR）抑制剂厄洛替尼最初对携带EGFR激活突变的非小细胞肺癌（NSCLC）患者有效，但大多数患者随后会产生获得性耐药。一种公认的耐药机制是通过肝细胞生长因子（HGF）-MET途径激活旁路信号。INC-280是一种MET小分子激酶抑制剂。我们试图证明INC-280对选定的NSCLC细胞系的活性，既作为单一药物，也与厄洛替尼联合使用，通过外源性HGF模拟MET上调。
方法
用单一药物INC-280或与厄洛替尼联合，在有或无HGF的情况下处理四种NSCLC细胞系（HCC827、PC9、H1666和H358）。通过细胞活力测定来测量药物治疗的活性。免疫印迹用于监测H1666、HCC827和PC9中EGFR/pEGFR、MET/pMET、GAB1/pGAB1、AKT/pAKT和ERK/pERK的表达以及凋亡标志物（PARP和半胱天冬酶-3裂解）。
结果
作为单一药物，尽管INC-280在低至10 nM的浓度下就能有效抑制MET激酶活性，但其细胞毒性极小。添加HGF可防止厄洛替尼诱导的细胞死亡。在HGF介导的厄洛替尼耐药模型中添加INC-280可恢复所有测试细胞系对厄洛替尼的敏感性，这与PARP和半胱天冬酶-3的裂解有关。在这些模型中，INC-280治疗足以在有HGF存在的情况下恢复厄洛替尼诱导的对MET、GAB1、AKT和ERK的抑制。
结论
尽管MET抑制剂INC-280单独对细胞生长没有明显影响，但它能够恢复对厄洛替尼的敏感性，并在因HGF而对厄洛替尼耐药的NSCLC模型中促进凋亡。这些数据为正在进行的厄洛替尼加INC-280用于EGFR突变的NSCLC的1期临床试验提供了临床前依据。
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