Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Mol Cancer Ther. 2013 Aug;12(8):1429-41. doi: 10.1158/1535-7163.MCT-13-0016. Epub 2013 May 29.
The MET and EGFR receptor tyrosine kinases (RTK) are often coexpressed and may cross-talk in driving the development and progression of non-small cell lung carcinoma (NSCLC). In addition, MET amplification is an alternative resistance mechanism for escaping EGFR-targeted therapy. To assess the benefits of combined targeting of MET and EGFR for treating NSCLCs, we investigated the activities of these two RTK pathways in NSCLC cell lines and evaluated their responses to SGX523 and erlotinib, the small-molecule kinase inhibitors of MET and EGFR, respectively. We showed that MET interacts with and cross-activates EGFR in MET-amplified or -overexpressed cells. The inhibition of both MET and EGFR results in maximal suppression of downstream signaling and of cell proliferation when their ligands are present. Furthermore, we showed that SGX523 plus erlotinib strengthens anticancer activity in vivo in a cellular context-dependent manner. The combination led to the regression of H1993 tumors by enhancing the suppression of proliferation and inducing apoptosis, whereas H1373 tumor growth was significantly reduced by the combination via suppression of proliferation without inducing apoptosis. SGX523 alone was sufficient to achieve near-complete regression of EBC-1 tumors; its combination with erlotinib strongly inhibited the viability of a population of insensitive cells emerging from an SGX523-treated EBC-1 tumor recurrence. Our data suggest that inhibition of both MET and EGFR can enhance anticancer effects against NSCLCs in a context-dependent manner and thus provide a strong rationale for combining MET and EGFR inhibitors in treating NSCLCs.
MET 和 EGFR 受体酪氨酸激酶（RTK）经常共表达，并可能通过交叉对话来驱动非小细胞肺癌（NSCLC）的发展和进展。此外，MET 扩增是逃避 EGFR 靶向治疗的另一种耐药机制。为了评估联合靶向 MET 和 EGFR 治疗 NSCLC 的益处，我们研究了这两种 RTK 通路在 NSCLC 细胞系中的活性，并评估了它们对 MET 和 EGFR 的小分子激酶抑制剂 SGX523 和 erlotinib 的反应。我们表明，MET 在 MET 扩增或过表达的细胞中与 EGFR 相互作用并交叉激活 EGFR。当存在它们的配体时，抑制 MET 和 EGFR 会最大程度地抑制下游信号转导和细胞增殖。此外，我们表明，在细胞背景依赖的方式下，SGX523 加 erlotinib 增强了体内的抗癌活性。该组合通过增强增殖抑制和诱导细胞凋亡导致 H1993 肿瘤消退，而通过抑制增殖而不诱导细胞凋亡，该组合显著降低了 H1373 肿瘤的生长。SGX523 本身足以使 EBC-1 肿瘤几乎完全消退；它与 erlotinib 的组合强烈抑制了从 SGX523 处理的 EBC-1 肿瘤复发中出现的一组不敏感细胞的活力。我们的数据表明，抑制 MET 和 EGFR 均可增强 NSCLC 以背景依赖的方式的抗癌作用，因此为联合使用 MET 和 EGFR 抑制剂治疗 NSCLC 提供了强有力的理由。
