Abstract 4440: Identification and characterization of small molecule inhibitors that radiosensitize K-RAS mutant rectal cancers.

Abstract

Abstract Around 40% of rectal cancers harbor activating K-RAS mutations, and these mutations are associated with resistance to chemoradiotherapy. We aimed to identify small molecule inhibitors (SMIs) that synergize with ionizing radiation (IR) (“radiosensitizers”) that could be incorporated into current treatment strategies for K-RAS mutant locally advanced rectal cancer (LARC) patients. We first optimized a high-throughput assay for measuring individual and combined effects of SMIs and IR that produces similar results to the gold standard colony formation assay. Using this screening platform and K-RAS mutant rectal cancer cell lines, we tested SMIs targeting diverse signaling pathways for radiosensitizing activity and then evaluated our top hits in follow-up experiments. The two most potent radiosensitizers were the Chk1/2 inhibitor AZD7762 and the PI3K/mTOR inhibitor BEZ235. The chemotherapeutic agent 5-fluorouracil (5-FU), which is used to treat LARC, synergized with AZD7762 and enhanced radiosensitization by AZD7762 but not by BEZ235. This study is the first to compare different SMIs in combination with IR for the treatment of K-RAS mutant rectal cancer, and our findings suggest that Chk1/2 inhibitors should be evaluated in new clinical trials for LARC. Citation Format: Laura B. Kleiman, Angela Krebs, Stephen Kim, Theodore S. Hong, Kevin M. Haigis. Identification and characterization of small molecule inhibitors that radiosensitize K-RAS mutant rectal cancers. [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 4440. doi:10.1158/1538-7445.AM2013-4440