Abstract LB-299: Comprehensive preclinical evaluation of VE-822, the first ATR-targeted drug candidate: a novel approach to transforming the efficacy of DNA damaging agents.

Abstract

Abstract DNA damaging agents have been the cornerstone of cancer therapy for decades yet they provide only modest benefit for most patients. For example, standard of care for patients with non-small cell lung cancer (NSCLC) is dominated by the use of platinating drugs and ionizing radiation (IR), however outcome remains very poor with 5-year survival rates of <15% for patients that present with advanced disease. Such poor responses to DNA damaging treatment reflects, in part, the efficient repair of DNA damage via a complex signaling and repair network known as the DNA damage response (DDR). The DDR detects double strand breaks and replication stress, the most lethal forms of DNA damage, and acts to enforce checkpoints to halt cell cycle progression, and to stimulate repair. Key regulators of the DDR are the phosphoinositol 3-kinase-like serine/threonine protein kinase (PIKK) family members ATR and ATM. Recent pre-clinical data has suggested that a reliance on ATR for survival from DNA damage may be a common feature of cancer. This can arise either as a consequence of high replicative stress, for example from expression of certain oncogenes, from a hypoxic microenvironment, or from defects elsewhere in DNA damage surveillance and repair pathways. Most notably inhibition of ATR has been shown to be synthetic lethal with loss of the ATM-p53 pathway. In NSCLC defective ATM signaling, from loss of ATM expression or from defects in p53 has been reported in about 50% of tumors. Here we describe the comprehensive in vitro and in vivo profile for VE-822 a novel highly potent and selective inhibitor of ATR. VE-822 potently inhibits ATR in biochemical assays with Ki <0.3nM and in cell assays with IC50 of 20nM. Against a large panel of NSCLC lines, low concentrations of VE-822 sensitized many lines to the cytotoxic effects of multiple DNA damaging agents; for example >90% of lines showed >3-fold shifts in IC50 for cisplatin in the presence of VE-822, with ~50% of lines showing >10-fold increases in cisplatin cytotoxicity. In contrast normal cells tolerate inhibition of ATR. In a panel of mouse xenograft models, derived from various primary human NSCLC tumor tissues, oral or IV administration of VE-822 strongly sensitized tumors to cisplatin treatment. In many cases, combinations including VE-822 led to tumor regression or extensive tumor growth delay. Inhibition of ATR activity and accumulation of DNA damage by VE-822 was observed coincident with efficacy. When administered alone or in combination with cisplatin VE-822 was well tolerated in mice at doses that block ATR activity. These data support the potential for ATR inhibitors to substantially increase the efficacy of standard-of-care agents in diseases such as NSCLC. Citation Format: Diane Boucher, Peter Charlton, Jean-Damien Charrier, Brinley Furey, Yong Gu, Amy Hall, Brian Hare, Howard Li, Sean Milton, Cheryl Murphy, Philip Reaper, Darin Takemoto, Taturo Udagawa, Yuxin Wang, Mark Wood, John Pollard. Comprehensive preclinical evaluation of VE-822, the first ATR-targeted drug candidate: a novel approach to transforming the efficacy of DNA damaging agents. [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 LB-299. doi:10.1158/1538-7445.AM2013-LB-299