Abstract 3425: Chk1 inhibitor targets replicative stress in melanomas.

Abstract

Abstract There are few effective treatments for metastatic melanoma. Chk1 inhibitors are being trialed for their efficacy in enhancing conventional chemotherapeutic agents, but their effectiveness as single agents is relatively unexplored. We have examined the effectiveness of two novel Chk1 selective inhibitors, AR-323 and AR-678, in a large panel (40) of melanoma cell lines and normal cell types in vitro, and investigated the mechanism promoting their cytotoxicity in the drug-sensitive cell lines. We demonstrate that these drugs display single agent activity, with IC50s in the nanomolar range. The drugs produce cytotoxic effects in cell lines that are most sensitive to these drugs, whereas normal cells are only sensitive to these drugs at the higher concentrations where they have cytostatic activity. The cytotoxic effect is related to inhibition of S phase Chk1 which drives cells prematurely from late S phase, resulting in apoptosis either prior to or during an aberrant mitosis. Time lapse imaging has shown that the timing of cell death is related to the drug sensitivity of the cell line. The sensitivity to the Chk1 inhibitors was correlated with the level of endogenous DNA damage indicating replicative stress, and increasing endogenous replicative stress increased drug sensitivity. Chk1 inhibitors are viable single agent therapies which target melanoma cells with high levels of endogenous DNA damage. This sensitivity suggests that Chk1 is a critical component of an adaptation to replicative stress in these cells. It also suggests that markers of DNA damage may be useful in identifying the melanomas and potentially other tumour types that are more likely to be sensitive to Chk1 inhibitors as single agents. Citation Format: Brian G. Gabrielli, Kelly Brooks, Brooke Edwards, James Chen, Sandra Pavey. Chk1 inhibitor targets replicative stress in melanomas. [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 3425. doi:10.1158/1538-7445.AM2013-3425