Abstract AP31: ATR INHIBITION TARGETS TREATMENT RESISTANT OVARIAN CANCER

Abstract

Abstract Introduction: Although new treatments for ovarian cancer have been developed with the introduction of Poly (ADP-ribose) polymerase inhibitors (PARPi) to standard of care platinum chemotherapy, the majority of tumors acquire drug resistance. Strategies to circumvent PARPi and platinum resistance are needed and our study addresses this gap. We hypothesize that PARPi resistant tumors are dependent on ATR/CHK1 for DNA repair, and by targeting ATR in combination with PARPi would be more effective in eradicating tumor growth. Experimental Procedures: Drug resistant cells were developed by long term treatment of PEO1 (BRCA2 mutant) and JHOS4 (BRCA1 mutant) ovarian cancer cells with PARPi (AZD2281) or Carboplatin. Cell viability, colony formation, cell cycle and apoptosis were evaluated. Homologous recombination was evaluated by Rad51 foci immuno staining. Replication fork asymmetry was counted by DNA combing assay. PARPi resistant orthotopic PDX models (germline BRCA1/ 2 mutant) were developed by long term treatment with PARPi. PDX developed from a platinum-resistant HGSOC patient with CCNE1 amplification was also tested to evaluate PARPi +/- ATRi. Whole genome sequencing, Reverse-Phase Protein Array Analysis (RPPA) and IHC were performed on cells and xenografts to evaluate for biomarkers of response. Results: ATR/CHK1 pathway was constitutively activated in treatment resistant cell lines. Monotherapy with ATRi alone in vitro modestly induced cell death and DNA damage in PARPi and platinum resistant cell lines. Treatment with ATRi in combination with PARPi is synergistic in reducing survival of these drug resistant cells. Combination treatment was more effective in targeting cell cycle mediators, and promoting apoptosis. HR was restored in PARPi and platinum treatment resistant PEO1 cells. ATRi treatment suppressed restored HR and increased stalled replication fork. PARPi and ATRi combination treatment was synergistic in causing tumor regression in PARPi/Carboplatin resistant PDX models. Conclusions: Our work suggests treatment resistant cells are more dependent on ATR/CHK1 pathway and ATR is a promising target for augmenting PARPi and platinum response in treatment resistant HGSOCs. Citation Format: Hyoung Kim, Erin George, Haineng Xu, Sergey Medvedev, Veena Jagannathan, Mark Morgan, Gordon Mills, Eric Brown, Fiona Simpkins. ATR INHIBITION TARGETS TREATMENT RESISTANT OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP31.