Mol Cancer Ther. 2013 Aug;12(8):1429-41.

Strengthening context-dependent anticancer effects on non-small cell lung carcinoma by inhibition of both MET and EGFR.

Zhang YW, Staal B, Essenburg C, Lewis S, Kaufman D, Vande Woude GF.

Van Andel Research Institute, Grand Rapids, MI 49503, USA.



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.

PMID: 23720767



Non-small cell lung cancer (NSCLC) accounts for more than 80% cases of lung cancer, which is the leading cause of cancer deaths, and the therapeutic options for advanced NSCLC are limited. Both EGFR and MET receptor tyrosine kinases (RTKs) are known to play important roles in the development and progression of NSCLC, and thus are optimal targets for cancer intervention. EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib have been approved for treating advanced NSCLC, whereas various inhibitors targeting MET are currently in clinical development. Although EGFR-TKIs have been proved to be effective for treating certain NSCLC, the benefit of such treatment is currently limited to patients whose tumors carry sensitive EGFR driver mutations or amplification. This leaves the majority of NSCLC patients without benefit from the EGFR-TKIs treatment, likely due to the availability of signaling driven by other RTKs such as MET. Frequent emergence of drug resistant tumors is another hurdle for treating patients with EGFR-TKI monotherapy, and aberrant MET activation is known to be one of the critical mechanisms causing the resistance. Thus, identifying therapeutic strategies that can overcome the shortcomings of EGFR-TKI monotherapy may broaden the clinical usage of such drugs and maximize the drug efficacy for treating NSCLC.

MET and EGFR are often co-expressed and may cross-talk to each other in the NSCLC cells, and thus we reasoned that simultaneously targeting MET and EGFR might achieve a better therapeutic outcome than that of individual inhibition. In this study, we explored the therapeutic feasibility of combining MET and EGFR inhibitors for treating NSCLC using preclinical tumor models. We demonstrated that combining SGX523 (MET inhibitor) and erlotinib significantly enhanced anti-cancer efficacies in cellular-context dependent manners (Figure 1), and provide a mechanistic understanding of why dual inhibition of EGFR and MET is a sound strategy for treating NSCLC.

Yu-Wen Zhang fig1Figure 1. Context-dependent anti-cancer effects by combined inhibition of MET and EGFR. (A) Enhanced inhibition of H1373 tumor growth by the combination of SGX523 and erlotinib. The combination resulted in enhanced antiproliferation without inducing apoptosis. Proliferation was determined by IHC staining of Ki67, and apoptosis was determined by the staining of cleaved caspase-3. (B) SGX523 and erlotinib combination led to H1993 tumor regression by enhancing antiproliferation and inducing apoptosis. (C) MET-addicted EBC-1 tumors were extremely sensitive to SGX523 alone but might utilize EGFR pathway to escape MET inhibition. EBC1-Sg3-H62 and EBC1-Sg3-H71 are two SGX523-resistant cell lines established from SGX523-treated EBC-1 recurrent tumors. These two resistant cell lines displayed increased EGFR activities (Western blot) and were less sensitive to SGX523; however, their viability was significantly decreased by SGX532 and erlotinib combination (CellTiter-Glo Luminescent Assay). D: (+) DMSO; S: (+) SGX523; E: (+) erlotinib; and SE: (+) SGX523 & erlotinib.

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