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

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.