Abstract 3797: AsiDNA abrogates acquired resistance to PARP inhibitors

Abstract

Abstract Purpose: PARP inhibitors (PARPi) are approved for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance remain a clinical hurdle, and several attempts failed to decrease this resistance. In the current study, we propose a novel therapeutic strategy, based on drug combination to abolish the onset of resistance to PARPi. Experimental design: We performed a set of experiments to induce resistance to PARPi and assess the impact of AsiDNA addition to decrease this resistance occurrence. AsiDNA is a double stranded DNA molecule (decoy oligo-nucleotide) that mimics double stranded DNA breaks (DSBs) to interfere with DNA repair, by over-activating a “false” signaling of DNA damage through DNA-PK and PARP enzymes. We characterized the effects of long term treatment with the PARPi olaparib and talazoparib on resistance selection in two different cell lines, BC227 and NCI-H446, and we further analyzed the effect of low doses of AsiDNA on the occurrence of acquired resistance to these PARPi. Finally, we addressed the mechanisms underlying resistance emergence and abrogation. Results: Long term exposure of cancer cells to PARPi induces the emergence of resistance in all the tested independent populations (11 BC227 independent populations and 3 NCI-H446 for talazoparib, 5 BC227 independent populations for olaparib), raising the question of the clinical benefit of long-term maintenance monotherapy with PARPi. Interestingly, double-treated populations with AsiDNA (2.5µM - low non cytotoxic dose) and talazoparib or olaparib showed a significant lower probability of resistance occurrence. In fact, 9/11 (or 5/5) BC227 populations treated with AsiDNA and talazoparib (or AsiDNA and olaparib) remained sensitive up to 5 cycles of treatment, and 3/3 NCI-H446 populations treated with AsiDNA and talazoparib. Interestingly, AsiDNA is also able to partially revert talazoparib resistance in BC227 and NCI-H446 resistant populations. As described, PARP1, EZH2 and/or 53BP1 protein expression loss or reduction are important mechanisms leading to PARPi resistance. We confirmed in these experiments that treatments with PARPi significantly modify the expression and activity of these proteins and we demonstrated that co-treatment with AsiDNA inhibits these changes. These results indicate that AsiDNA may abrogate and reverse PARPi acquired resistance by the normalization of involved protein expression and activity. Conclusion: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate drug-driven PARPi resistance abrogation. As PARPi have obtained FDA approval, and AsiDNA is being currently tested in a clinical trial, a potential exists for a rapid clinical confirmation of AsiDNA-induced PARPi resistance abrogation and reversion. Citation Format: Wael Jdey, Pauline Lascaux, Françoise Bono. AsiDNA abrogates acquired resistance to PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3797.