Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.
INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.
Mol Cancer Ther. 2017 Oct;16(10):2107-2119. doi: 10.1158/1535-7163.MCT-17-0112. Epub 2017 Jun 15.
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines and in subcutaneous and orthotopic tumor models In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. .
几种针对 HGF/MET 信号的治疗药物正在进行临床开发，作为单一药物或联合使用，特别是在非小细胞肺癌（NSCLC）中与抗 EGFR 治疗联合使用。然而，尽管越来越多的数据支持 MET、辐射和癌症进展之间存在联系，但临床上尚无关于 MET 靶向药物与放疗联合使用的相关数据。S49076 是一种口服 ATP 竞争性 MET、AXL 和 FGFR1-3 受体抑制剂，目前正在进行 I/II 期临床试验，与吉非替尼联合用于其肿瘤对 EGFR 抑制剂耐药的 NSCLC 患者。在这里，我们研究了 S49076 对 MET 信号、细胞增殖和克隆存活的影响，在 MET 依赖性（GTL16 和 U87-MG）和 MET 非依赖性（H441、H460 和 A549）细胞中。我们的数据表明，S49076 通过抑制 MET 在低剂量下对 MET 依赖性细胞发挥细胞毒性作用，而在更高但临床相关剂量下通过靶向 Aurora B 抑制 MET 非依赖性细胞的生长。此外，我们发现 S49076 提高了两种 MET 依赖性和 MET 非依赖性细胞系以及皮下和原位肿瘤模型中的放疗抗肿瘤疗效。总之，我们的研究表明，S49076 具有双重抗肿瘤活性，可与放疗联合用于治疗 MET 依赖性和 MET 非依赖性肿瘤。这些结果支持在临床试验中评估 S49076 与放疗联合治疗，而无需根据肿瘤 MET 依赖性状态对患者进行选择。
