Purpose: Gastric cancer remains a major global health threat and most patients with advanced stage disease require chemotherapy. The development of drug resistance is a major obstacle in the treatment of gastric cancer and only few effective therapies for combating chemoresistance are currently available. It has been demonstrated that a small subset of cancer cells with stem cell properties, referred to as “cancer stem cells” (CSCs), survive intensive anticancer therapies better than proliferating progenitor cells or differentiated tumor cells. CSCs have been reported to be postulated mediators of chemoresistance, so it might be important to comprehend the drug resistance mechanisms of CSCs to develop a promising therapy to combat chemoresistance. The stemness signal might be associated with the chemosensitivity of CSCs. In the present study, we analyzed the effect of c-Met inhibitors on the chemosensitivity of stem-like cancer cells in gastric cancer. We demonstrated that a c-Met inhibitor synergistically increased the antitumor activity of SN38 in CSCs. To determine mechanisms underlying this observed synergism, we observed that a c-Met inhibitor combined with SN38 also led to a significant increase in UGT1A1 and its subsequent interaction with apoptosis-related genes, i.e., bcl-2 and caspase-6.

Experimental Design: We used three gastric cancer cell lines and three side population (SP)-enriched cell lines. We used three signal inhibitors, c-Met inhibitor SU11274, GSK3β inhibitor AR-A014418, and mTOR inhibitor rapamycin, and five anticancer drugs. We examined the combined effects of signal inhibitors and anticancer drugs on proliferation, mRNA expression, and cell cycle.

Results: The IC50 of irinotecan, oxaliplatin, taxol, and gemcitabine in SP cells were 10.5, 2.0, 2.8, and 2.0 times higher than their parent cells, respectively. In contrast, the IC50 of 5-fluorouracil did not differ between the two cell lines. There was a synergistic anti-proliferative effect with a combination of c-Met inhibitor and SN38 in SP cells. In contrast, the GSK3β inhibitor and mTOR inhibitor had no synergistic effects in combination with any anticancer drugs. The SP cell lines had higher expression levels of UGT1A1, ABCG2, and ABCB1 than their parent cell lines, while the c-Met inhibitor significantly decreased the expression of UGT1A1, but not ABCG2 and ABCB1. G0-phase of SP cells was higher than their parent cells. c-Met inhibition induced S-phase arrest in SP cells.

Conclusions: CSCs are associated with multiresistance during chemotherapy. c-Met inhibitors could be a novel strategy to overcome chemoresistance. c-Met inhibitor may be a promising target molecule for irinotecan-based chemotherapy of gastric cancer. A UGT1A1 alteration might be involved in the irinotecan refractory process in CSCs.

Citation Format: Masakazu Yashiro, Tatsunari Fukuoka, Haruhito Kinoshita, Takafumi Nishii, Tsuyoshi Hasegawa, Taro Matsuzaki, Tamami Morisaki, Kosei Hirakawa. A c-Met inhibitor increases the chemosensitivity of cancer stem cells to the irinotecan active metabolite SN38 in gastric carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 225. doi:10.1158/1538-7445.AM2013-225