Abstract 2549: Efficacy of the Chk1 inhibitor PF-00477736 and pemetrexed in human mesothelioma

Abstract

Abstract Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy with the median survival of less than 1 year from diagnosis. Pemetrexed (PTX), a multi-targeted antifolate drug in combination with cisplatin, has been used as front-line treatment. PTX-treatments causes S-phase cell cycle arrest allowing cancer cells to repair damaged DNA critical for cell survival and proliferation. The Chk1 kinase, a central regulator of cell cycle progression and a principal mediator of cell cycle checkpoints in response to genotoxic stress is overexpressed in mesothelioma. We evaluated the in-vitro activity of the Chk1 kinase inhibitor, PF-00477736, in combination with PTX in MPM. PF-00477736 treatments abrogated the PTX-induced S-phase cell cycle arrest and enhanced cytotoxicity of PTX in a dose-dependent manner (∼81% cell proliferation inhibition, vs. ∼13% with PTX alone). PTX and PF-00477736 treatments alone enhanced the levels of γH2AX (6% and 16%, respectively), however, their combination had significantly higher effect (∼60% increase) compared to control cells. These results suggest that when Chk1 is inhibited, PTX-induced replication stress is converted into additional DNA damage due to checkpoint abrogation and lack of DNA repair. The sensitization of mesothelioma cells to PTX by PF-00477736 was also associated with a marked increase in apoptosis (∼11-fold increase compared to PTX of PF-00477736 treatments alone). Collectively, these results show a therapeutic potential of combining Chk1 inhibitors and PTX for the treatment of mesothelioma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2549. doi:10.1158/1538-7445.AM2011-2549