Friese-Hamim Manja, Bladt Friedhelm, Locatelli Giuseppe, Stammberger Uz, Blaukat Andree
Translational In Vivo Pharmacology, Merck KGaADarmstadt, Germany.
Translational and Biomarker Research, Merck KGaADarmstadt, Germany.
Am J Cancer Res. 2017 Apr 1;7(4):962-972. eCollection 2017.
Non-small cell lung cancer (NSCLC) sensitive to first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) often acquires resistance through secondary EGFR mutations, including the T790M mutation, aberrant c-Met receptor activity, or both. We assessed the ability of the highly selective c-Met inhibitor tepotinib to overcome EGFR TKI resistance in various xenograft models of NSCLC. In models with EGFR-activating mutations and low c-Met expression (patient explant-derived LU342, cell line PC-9), EGFR TKIs caused tumors to shrink, but growth resumed upon cessation of treatment. Tepotinib combined with EGFR TKIs delayed tumor regrowth, while tepotinib alone was ineffective. In patient explant-derived LU858, which has an EGFR-activating mutation and expresses high levels of c-Met/HGF, EGFR TKIs had no effect on tumor growth. Tepotinib combined with EGFR TKIs caused complete tumor regression and tepotinib alone caused tumor stasis. In cell line DFCI081 (activating EGFR mutation, c-Met amplification), EGFR TKIs were ineffective, whereas tepotinib alone induced complete tumor regression. Finally, in a 'double resistant' EGFR T790M-positive, high c-Met model (cell line HCC827-GR-T790M), the EGFR TKIs erlotinib, afatinib, and rociletinib, as well as tepotinib as a single agent or in combination with erlotinib or afatinib, slowed tumor growth, but only tepotinib in combination with rociletinib induced complete tumor regression. We conclude that tepotinib can overcome acquired resistance to EGFR TKIs. Based on these data, clinical trials of tepotinib in combination with EGFR TKIs in patients with NSCLC with acquired resistance to first-generation EGFR TKIs are warranted.
对第一代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）敏感的非小细胞肺癌（NSCLC）通常会通过继发性EGFR突变产生耐药性，这些突变包括T790M突变、异常的c-Met受体活性或两者兼有。我们评估了高度选择性的c-Met抑制剂替泊替尼在各种NSCLC异种移植模型中克服EGFR TKI耐药性的能力。在具有EGFR激活突变且c-Met表达低的模型（患者外植体来源的LU342、细胞系PC-9）中，EGFR TKIs使肿瘤缩小，但治疗停止后肿瘤又重新生长。替泊替尼与EGFR TKIs联合使用可延迟肿瘤再生长，而单独使用替泊替尼则无效。在具有EGFR激活突变且表达高水平c-Met/HGF的患者外植体来源的LU858中，EGFR TKIs对肿瘤生长没有影响。替泊替尼与EGFR TKIs联合使用可使肿瘤完全消退，单独使用替泊替尼则使肿瘤停滞生长。在细胞系DFCI081（激活EGFR突变、c-Met扩增）中，EGFR TKIs无效，而单独使用替泊替尼可诱导肿瘤完全消退。最后，在一个“双重耐药”的EGFR T790M阳性、高c-Met模型（细胞系HCC827-GR-T790M）中，EGFR TKIs厄洛替尼、阿法替尼和罗西替尼，以及单独使用替泊替尼或与厄洛替尼或阿法替尼联合使用，均减缓了肿瘤生长，但只有替泊替尼与罗西替尼联合使用可诱导肿瘤完全消退。我们得出结论，替泊替尼可以克服对EGFR TKIs的获得性耐药。基于这些数据，有必要对第一代EGFR TKIs获得性耐药的NSCLC患者进行替泊替尼与EGFR TKIs联合使用的临床试验。
