Abstract 1066: PARP inhibitor rucaparib in combination with imipridones ONC201 or ONC212 demonstrates preclinical synergy against BRCA1/2-deficient breast, ovarian, and prostate cancer cells

Abstract

Abstract BRCA1/2 genes encode proteins that mediate homologous recombination and repair (HRR). BRCA1/2 mutations increase risk of breast, ovarian, prostate and other cancers. BRCA1/2 mutated tumor cells are sensitive to PARP inhibitors (PARPi), that cause DNA replication fork to collapse. Approximately 40% of patients develop PARPi resistance through different mechanisms. One of the mechanisms of PARPi resistance is through P13k/Akt pathway activation. Imipridones are TRAIL-inducing compounds which are PERK-independent activators of the integrated stress response, and dual inhibitors of Akt/ERK. We hypothesized that combining imipridones with PARPi would overcome PARPi resistance due to Akt activation. PARPi also sensitize various solid tumors to recombinant TRAIL and DR5 agonist antibodies thereby further suggesting possible synergies between imipridones and PARPi. Our lab previously showed efficacy of imipridone ONC201 in BRCA-deficient cancer cells and potential synergy with olaparib (2017 AACR annual meeting abstract), without further investigating potential synergistic mechanisms. We explored combination drug synergy of rucaparib (PARP inhibitor) and imipridones (ONC212 and ONC201) in BRCA1/2-deficient breast, ovarian and prostate cancer cell lines. CellTiterGLO viability assays were performed after 72 hours to demonstrate synergistic effects of combination treatment. Western blots were performed to investigate the effect of combination treatment on the Akt pathway, as well as expression of cellular metabolic stress protein ATF4. Cytokine profiling using the Luminex 200 technology was used to study the effect of treatment on the tumor microenvironment. Combination treatment (rucaparib and ONC212, rucaparib and ONC201) in BRCA–deficient cell lines (HCC1937, PEO1, KURAMOCHI, 22RV1, LNCAP) showed synergistic reduction in cell viability. In the HCC 1937 cell line, combination studies of rucaparib-ONC212 and rucaparib-ONC201 showed a synergystic effect, as calculated by Compusyn software, combination indexes below one were observed at concentration of 0.29-37.5 of µM rucaparib with ONC201 at 1.25-5 µM and ONC212 6.25-50 nM with the best combination index of 0.7 for rucaparib-ONC201 combination and 0.31 for rucaparib-ONC212. We similarly observed synergy in other cell lines with combination treatment. Western blot analysis of rucaparib-ONC212 combination showed total Akt protein reduction and an increase in ATF4 consistent with the synergistic effects. Further studies are ongoing to characterize possible mechanisms and effects of PARP inhibitor-imipridone combination treatment on immune-mediated killing. Our findings identify novel PARP inhibitor-imipridone therapy combinations that can be further developed for treatment of BRCA1/2 deficient cancers. Citation Format: Maryam Ghandali, Kelsey E. Huntington, praveen Srinivasan, Don S. Dizon, Stephanie L. Graff, Benedito A. Carneiro, Wafik S. El-Deiry. PARP inhibitor rucaparib in combination with imipridones ONC201 or ONC212 demonstrates preclinical synergy against BRCA1/2-deficient breast, ovarian, and prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1066.