c-Met targeting enhances the effect of irradiation and chemical agents against malignant colon cells harboring a KRAS mutation.

Abstract

Although EGFR-targeted therapy has been beneficial to colorectal cancer patients, several studies have showed this clinical benefit was restricted to patients with wild-type KRAS exon 2 colorectal cancer. Therefore, it is crucial to explore efficient treatment strategies in patients with KRAS mutations. c-Met is an emerging target for the development of therapeutics against colorectal cancer. In this study, we first used the SW620 cell line, which has an activating KRAS mutation, to generate a stable cell line with conditional regulation of c-Met, which is an essential gene for growth and an oncogene. Using this approach, we evaluated the benefits of combined c-Met-targeted therapy with irradiation or chemical agents. In this cell line, we observed that the proliferation and migration of SW620 cells were reduced by the induction of c-Met shRNA. Furthermore, c-Met knockdown enhanced the anti-proliferative effects of 5-FU and Taxol but not cisplatin, irinotecan or sorafenib. These enhancements were also observed in another colon cancer cells line HCT-116, which also has a KRAS mutation. The response of SW620 cells to irradiation was also enhanced by c-Met knockdown. This method and obtained data might have important implications for exploring the combinatory effects of targeted therapies with conventional medications. Moreover, the data suggested that the combination of c-Met-targeted therapy with chemotherapy or irradiation might be an effective strategy against colorectal cancer harboring a KRAS mutation.