Abstract 3711: Pre-clinical combinations of ATR and PARP inhibitors: Defining target patient populations and dose schedule
Authors: Pollard John , Reaper Phil , Peek Adele , Hughes Stuart , Djeha Hakim , Cummings Steven , Larbi Karen , Penney Marina , Sullivan Jim , Takemoto Darin , DeFranco Chris 
Published: July 2016

Defective DNA damage repair, leading to genomic instability, is a common event during tumorigenesis. Despite enabling the persistence of mutations, any of which can confer a growth advantage to the nascent tumor, these defects place an Achilles Heel reliance on remaining repair pathways for survival from DNA damage. The protein kinases ataxia telangiectasia mutated (ATM) and ATM and Rad3 related (ATR) are key mediators of a DNA damage response activated by DNA damage during the S and G2 phases of cell cycle. Together they signal a series of cellular responses including activation of checkpoints and repair by homologous recombination. Loss of ATM pathway function frequently occurs in cancer, commonly from loss of function mutations in the tumor suppressor, p53, a substrate of ATM. This leads to a reliance on ATR that can be exploited for therapeutic benefit. Activation of ATR, by generation of S-phase DNA damage (replication stress, [RS]), can arise from treatment with DNA damaging drugs and certain targeted therapies such as inhibitors of poly ADP ribose polymerase (PARP). PARP is an enzyme involved in several DNA repair pathways, including base excision repair. Some PARP inhibitors have been shown to form an irreversible complex with DNA, potentially generating a direct RS lesion. While initial data indicates that inhibition of ATR and PARP is synergistic in some cancer cells, a comprehensive assessment has not been reported.

Inhibition of ATR was cytotoxic in combination with PARP inhibitors against many cancer, but not non-cancer, cells. This effect was observed with multiple PARP inhibitors irrespective of their potential to form a DNA complex. In large cell panels of over 100 cancer cell lines, greater synergy was observed for the combination of an ATR and PARP inhibitor in cell lines with mutation of the TP53 gene. This was confirmed in isogenic cell lines depleted for ATM or p53, and is consistent with the profile of ATR and DNA damaging drug combinations. Furthermore, a triple combination of a PARP inhibitor, ATR inhibitor and the DNA damaging drug, cisplatin, retained cancer cell specific cytotoxic activity. In vitro dose-scheduling studies with the doublet of a PARP and ATR inhibitor showed optimal activity was achieved with transient concurrent exposure to both agents. This schedule contrasts with that for ATR inhibitors in combination with DNA damaging drugs where sequential dosing was optimal. In a mouse xenograft model concurrent dosing on a twice-weekly schedule was effective and well-tolerated.

These data demonstrate the potential of combining ATR and PARP inhibitors in patients with p53 defective tumors. An optimal dose schedule was defined from cell and mouse studies. Together the data support clinical evaluation of ATR and PARP inhibitor combinations.

Citation Format: John Pollard, Phil Reaper, Adele Peek, Stuart Hughes, Hakim Djeha, Steven Cummings, Karen Larbi, Marina Penney, Jim Sullivan, Darin Takemoto, Chris DeFranco. Pre-clinical combinations of ATR and PARP inhibitors: Defining target patient populations and dose schedule. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3711.