Abstract C204: Inhibition of c‐Met signaling in combination with cisplatin and 5‐fluorouracil significantly enhances antitumor effects in gastric cancer models

Gastric cancer is currently the second most frequent cancer‐related cause of death with an incidence rate of approximately one million cases annually. The present worldwide standard of care treatment regimen for gastric cancer is the combination of 5‐fluorouracil (5‐FU) and platinum analog (cisplatin). Many receptor tyrosine kinases are deregulated in gastric cancer including erbB2, c‐Met, and EGFR. The purpose of our study was to dissect the role of c‐Met signaling in gastric cancer and test the effects of our c‐Met inhibitor (MK‐8033) alone and in combination with the standard of care agents 5‐FU and cisplatin. As a monotherapy, MK‐8033 potently inhibited proliferation in a panel of gastric cancer cell lines in vitro . When administered simultaneously with cisplatin and 5‐FU, the effects of the combination were diverse, ranging from additive to antagonistic. Altering the treatment schedule by the addition of 5‐FU and cisplatin prior to MK‐8033 resulted in an overall combination benefit across the panel. In a gastric cancer xenograft model, while MK‐8033 alone significantly inhibited tumor growth progression, the co‐administration of 5‐FU and cisplatin with MK‐8033 showed greater benefit than either the monotherapy or the standard regimen. In vitro cell cycle and survival analysis support the observed in vivo data, and provides a mechanistic rationale for the observed combination benefit. Our data suggest the combination of c‐Met inhibitors with standard of care agents 5‐FU and cisplatin may be beneficial in gastric cancer patients with activated c‐Met signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C204.