Abstract 2510: Efficacy of the Chk1 inhibitor SCH900776 at abrogating cell cycle arrest and enhancing DNA damage-induced cytotoxicity: Comparison with UCN-01

Abstract

Abstract Many anticancer agents damage DNA and arrest cell cycle progression primarily in S or G2 phase of the cell cycle depending on drug concentration. Previous studies with the topoisomerase I inhibitor SN38 have demonstrated the efficacy of the Chk1 inhibitor UCN-01 to overcome arrest forcing cells through S, G2 and lethal mitosis. UCN-01 was limited in clinical trials by high plasma protein binding; as a consequence many alternate Chk1 inhibitors have now been developed. SCH900776 is a novel Chk1 inhibitor entering Phase II clinical trials. SCH900776 inhibits Chk1 and overcomes SN38-mediated S and G2 arrest at 300 nM in several carcinoma cell lines which is comparable to UCN-01 at 50 nM. While both Chk1 inhibitors accelerated the rate of cell killing induced by SN38, neither enhanced the overall cell killing. Similarly, no overall sensitization to cisplatin was observed. In contrast, both Chk1 inhibitors induced dramatic sensitization of cells to antimetabolite-induced damage. For example, inhibition of Chk1 sensitized MDA-MB-231 cells to hydroxyurea with the 50% growth inhibitory concentration decreasing from 3 mM to 30 µM, a 100 fold sensitization. Importantly, concentrations of hydroxyurea that exhibited no activation of a checkpoint and no growth inhibition alone were sensitized by inhibition of Chk1. SCH900776 also induced a 50-fold sensitization to cytarabine, 10 fold sensitization to gemcitabine, but no sensitization to 5-fluorouracil. Hence, this sensitization does not extend to all antimetabolites. The 100-fold sensitization to hydroxyurea appeared to require complete inhibition of Chk1 (2 µM 776), although 10-fold sensitization to hydroxyurea was still observed at 200 nM SCH900776. In an MDA-MB-231 derivative expressing shRNA that resulted in almost undetectable levels of Chk1, the full level of sensitization to hydroxyurea could be achieved at 200 nM SCH900776 demonstrating that the response of tumors may vary with the endogenous level of Chk1. We are currently comparing the differential response of a panel of carcinoma cell lines and find some that are sensitized to hydroxyurea up to 100-fold at 200 nM SCH900776, although there appear to be determinants other than the Chk1 levels. These results can be extrapolated to suggest that marked differences in efficacy of SCH900776 can be expected in patients. It will be important to define the parameters of response as these may facilitate selection of patients most likely to respond to combination therapy with Chk1 inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2510.