Abstract C209: Inhibition of both c-Met and EGFR signaling shows synergistic antitumor activity in non-small cell lung cancer model

Abstract

Abstract c-Met and ErbB family of receptors including EGFR, ErbB-2, ErbB-3 and ErbB-4 are co-expressed in many human tumors including Non-Small Cell Lung Cancers (NSCLC). Several reports suggest that the activation of c-Met and ErbB family receptors is associated with poor prognosis in multiple tumors types. Recently it has been shown that activation of c-Met is common in Erlotinib and Gefitinib-resistant NSCLC patients. Combining c-Met and EGFR inhibitors has been proposed as a strategy for treatment in EGFR inhibitor-refractory lung cancers. To understand the cooperation of these pathways, we used a c-Met activated human NSCLC cell line (EBC-1), where EGFR signaling network is also active. In vitro treatment of EBC-1 cells with a combination of Erlotinib and MK-8033 (an inhibitor of c-Met and RON kinases) resulted in greater growth inhibition relative to treatment with either agent alone. In order to validate these in vitro data, we have tested MK-8033 and EGFR inhibitors (Erlotinib and Gefitinib) in vivo. The data suggests the effect of MK-8033 with Gefitinib or Erlotinib on tumor growth is greater when combined as compared to monotherapy in this preclinical xenograft model. PK data suggests no drug-drug interaction of MK-8033 and EGFR inhibitor when administered together. Exposure of these agents was sufficient to inhibit both kinases in tumors. Our studies provide a rationale for the combination of MK-8033 and Erlotinib or Gefitinib in EGFRi refractory patients with NSCLC. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C209.