Abstract 2593: Combined ATR+PARP inhibition exhibits potent synergy in colorectal and pancreatic cancer cytotoxicity

Abstract

Abstract Precision medicine continues to expand treatment options for patients tailored to tumor phenotype. In homologous recombination (HR) deficient cancers like those with BRCA1/2-mutations, inhibition of poly (ADP-ribose) polymerase (PARP) has shown improved mortality compared to older gold standard therapies like DNA damaging agents. Unfortunately estimates upward of 40% of patients develop resistance to PARP inhibitor monotherapy during the course of their treatment. We explored potential synergistic drug combinations to re-sensitize tumors with acquired PARP inhibitor resistance in pancreatic and colorectal cancer. We hypothesized that dual inhibition of the DDR pathway through PARP and Ataxia telangiectasia and Rad3 related (ATR) inhibition would combine synergistically especially in cell lines with existing HR deficiencies through a synthetic lethality-mediated response. The ATR inhibitor Ceralasertib was selected for its potent antagonism of the DDR pathway, a key pathway associated with cell survival through DNA repair. Pancreatic and colorectal cell lines were carefully selected based on their varying mutational profiles to study differences in response to dual treatment. CellTiter-Glo® (CTG) was used after drug treatment to quantify IC-50. CTG synergy and combination indices were used to study drug combinations, and western blotting identified changes in protein expression among key mediators of cell survival and apoptosis. Colony forming assays and cytokine profiling using Luminex technology (and single cell cytokine profiling) were performed to study changes within the tumor microenvironment. We observed strong synergy and cytotoxicity in addition to increased apoptosis and cellular disassembly following treatment with dual ATR+PARP inhibition compared to monotherapy alone. Western Blot showed upregulation of cleaved PARP and cleaved Caspase 8 with combination therapy, and cytokine profiles provided insights into immune-suppressive versus stimulatory TME after drug treatment. There is potent synergy when ATR inhibitors are added to PARPi therapy in the context of pancreatic and colorectal cancers. Ongoing research efforts are further characterizing the mechanisms underlying these observed synergies in the same and additional tumor types such as prostate and ovarian cancer. Citation Format: Anna M. Ochsner, Kelsey E. Huntington, Lanlan Zhou, Benedito Carneiro, Wafik El-Deiry. Combined ATR+PARP inhibition exhibits potent synergy in colorectal and pancreatic cancer cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2593.