Abstract
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.
Highlights
Receptor tyrosine kinases (RTK) are important cellular components in many normal developmental and physiologic processes, but their aberrant activation can cause serious pathologic outcomes by contributing to cancer development and progression [1,2,3]
We have previously shown that the MET small-molecule kinase inhibitor SGX523 synergizes with the EGF receptor (EGFR) inhibitor erlotinib to suppress xenograft growth of the non–small cell lung cancer (NSCLC) cell line H596, which harbors a mutation in the juxtamembrane domain of MET [22]
To further understand the benefit of a combined MET- and EGFR-targeted therapy against NSCLCs, we investigated the effects of SGX523 and erlotinib on in vitro signal transduction and cell proliferation and on in vivo tumor growth of NSCLC cell lines having distinct cellular properties
Summary
Receptor tyrosine kinases (RTK) are important cellular components in many normal developmental and physiologic processes, but their aberrant activation can cause serious pathologic outcomes by contributing to cancer development and progression [1,2,3]. The benefit of such treatment appeared to be limited to patients carrying particular EGFR mutations or amplifications [8, 9] The ineffectiveness of these treatments for most NSCLC tumors is probably due to availability of other pathways, such as that of MET, which can bypass EGFR signaling to maintain tumor cell survival and growth. To overcome such alternative paths, a sound approach would be to use those drugs in conjunction with the targeting of other oncogenic drivers that can bypass EGFR inhibition
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