Abstract 1644: VX-970, the first-in-class inhibitor of the DNA damage repair enzyme ATR
Authors: John Pollard, Philip Reaper, Julie Jones, Christopher Barnes, Scott Gladwell, Stuart Hughes, Adele Peak, Hakim Djeha, Amy Hall, David Newsome, Yuxin Wang, Diane Boucher, Brenda Eustace, Yong Gu, Brian Hare, Mac Johnson, Sean Milton, Cheryl Murphy, Darin Takemoto, Crystal Tolman, Mark Wood, Brinley Furey, Marina Penney, Howard Li, Christopher Defranco, Mohammed Asmal, Scott Fields
Journal: Cancer Research (2015)

Abstract Proficient repair of DNA damage is important for cancer cell survival and is a leading cause for the poor response many patients experience when treated with DNA-damaging drugs or ionizing radiation. The protein kinase ataxia telangiectasia mutated and Rad3 related (ATR) regulates an important DNA damage response pathway that is most commonly activated by replication stress (RS). RS arises during S-phase when the cell's DNA replication machinery attempts to copy through an unresolved damage lesion. Such events are common after cells are treated with DNA-damaging agents. Unresolved RS often leads to double strand breaks, which in turn may cause DNA mutations, chromosomal rearrangements or cell death. Pre-clinical data suggests a reliance on ATR for survival is a common feature in cancer cells. This may occur when there are defects in other DNA damage repair pathways or high levels of background RS. VX-970 is the first potent (Ki &amp;lt;0.3nM) and highly selective ATR inhibitor to enter clinical trials (EUDRACT: 2012-003126-250). In pre-clinical studies, it markedly increases the cytotoxic activity of multiple DNA damaging agents across large panels of cancer cell lines. In contrast, normal cells tolerate inhibition of ATR by activating compensatory repair signaling for example the pathway mediated by ATM. Defects in this ATM pathway, most notably as a result of mutations in the TP53 gene that encodes p53 (a principle substrate for ATM) is found to be a predictive marker for cell sensitivity in cancer cell lines. In mouse xenograft models VX-970 strongly potentiates the anti-cancer activity of DNA damaging drugs that include cisplatin, carboplatin, irinotecan and gemcitabine. Combinations are generally well tolerated and have been shown to provide better anti-cancer activity than the cytotoxic alone at its MTD. In addition, VX-970 has marked cytotoxic activity when combined with inhibitors of PARP (base excision repair protein) in multiple cancer cell lines, but is well tolerated by normal cells. Emerging data suggests that the cancer cell specificity for this combination may again be associated, at least in part, with defective ATM-p53 pathway signaling. Finally, VX-970 has potential as a monotherapy since potent single agent cytotoxic activity is observed in certain cancer cell lines. The basis for sensitivity to monotherapy may require both defects in alternative repair pathways and high background replication stress levels. VX-970 is currently in Phase 1 clinical studies as monotherapy and in combination with gemcitabine, cisplatin and carboplatin. Note: This abstract was not presented at the meeting. Citation Format: John Pollard, Philip Reaper, Julie Jones, Christopher Barnes, Scott Gladwell, Stuart Hughes, Adele Peak, Hakim Djeha, Amy Hall, David Newsome, Yuxin Wang, Diane Boucher, Brenda Eustace, Yong Gu, Brian Hare, Mac Johnson, Sean Milton, Cheryl Murphy, Darin Takemoto, Crystal Tolman, Mark Wood, Brinley Furey, Marina Penney, Howard Li, Christopher Defranco, Mohammed Asmal, Scott Fields. VX-970, the first-in-class inhibitor of the DNA damage repair enzyme ATR. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1644. doi:10.1158/1538-7445.AM2015-1644