Abstract IA11: Discovery and characterization of potent and selective inhibitors of ATR kinase as anti-cancer agents

Abstract

Abstract DNA damaging agents, such as cisplatin, gemcitabine or ionizing radiation (IR), represent the cornerstone for the treatment of cancer. However, for many patients they provide only modest benefit. One reason for this is the presence of highly effective cellular processes that detect and repair damaged DNA. The kinase ataxia telangiectasia mutated (ATM) and rad3 related (ATR) is a key mediator for one such cellular repair process that responds to replication stress (RS). RS arises when the DNA replication machinery stalls, leading to production of ssDNA, which directly recruits ATR. This occurs at difficult to replicate sites of the genome, when nucleotides are limiting, or when the replication machinery encounters DNA lesions. RS levels are often elevated in cancer cells, for example due to expression of oncogenes that drive unregulated proliferation, an hypoxic environment, or from treatment with DNA damaging drugs and ionizing radiation (IR). Once recruited to sites of RS ATR mediates activation of cell cycle checkpoints, stabilization of the stalled replication fork and repair of damaged DNA by homologous recombination (HR). Unresolved RS often leads to lethal double strand breaks. Over the past few years a number of potent and selective inhibitors of ATR have been reported and are widely used as pre-clinical tools to assess ATR inhibition as an anti-cancer approach. In vitro, inhibition of ATR potentiates the cytotoxic activity of many DNA damaging drugs and IR in many cancer cell lines. In stark contrast non-cancer cells tolerate inhibition of ATR with just transient and rapidly reversible growth arrest. This ability to tolerate ATR inhibition has been attributed to activation of a compensatory damage response mediated by the ATR homolog ATM. Accordingly, defects in ATM pathway function, for example from loss of expression in ATM or defects in a principle ATM substrate, p53, can confer cell sensitivity to ATR inhibition. In human cancer cell line, and patient-derived tumor, mouse xenografts, ATR inhibition markedly enhances the efficacy of a range of DNA damaging chemotherapies and IR with minimal impact on body weight loss. ATR inhibition has also shown single agent activity in certain cancer cell lines that have high background RS levels from expression of oncogenes such as Ras, defects elsewhere in the DNA repair network (e.g., ERRC1), or reliance on the HR-dependent alternative lengthening of telomeres (ALT) mechanism of telomere maintenance. Finally, ATR inhibition has recently been shown to have benefit when combined with targeted agents that impair other components of the DNA damage response. The best characterized of these are inhibitors of poly ADP-ribose polymerase (PARP), which is involved in the repair of single strand breaks and replication fork dynamics. Three ATR inhibitors are in clinical development, progressing as monotherapy and in combination with DNA damaging drugs and IR. Preliminary evidence of clinical activity has recently been reported for the first-in-class agent VX-970. Citation Format: John R. Pollard. Discovery and characterization of potent and selective inhibitors of ATR kinase as anti-cancer agents. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA11.