Abstract 4531: The synergistic potential of PARP inhibitors and irinotecan in small cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is highly aggressive and associated with a poor prognosis. While effective treatment is limited after a relapse from platinum-based chemotherapy, recent research has identified novel pathway targets including DNA damage repair (DDR) pathway. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been currently evaluated for their efficacy as a monotherapy and in combination with other agents, such as immunotherapy. Methods: We evaluated the efficacy of combining PARPi and irinotecan in ten SCLC cell lines with diverse genetic backgrounds in the DDR genes. After treating the cells with three different PARPi in combination with irinotecan, we assessed cell viability and the combination effects. Furthermore, we confirmed protein changes in the DDR pathway through western blotting and measured the number of apoptotic cells using Annexin V staining. Results: In our experiments, talazoparib had the most potent effect at low concentrations, while olaparib and venadaparib showed more pronounced synergistic effects (average fold change of IC50: olaparib, 1649±4049; talazoparib, 25±34. 21; venadaparib, 336±596. 01; see Table). The combination of talazoparib or venadaparib with irinotecan led to a reduction of IC50 values to below 10 nM in 7 out of 10 tested cell lines. Three cell lines carrying BRCA mutations displayed a strong sensitivity to PARPi, whereas no significant correlation found with alterations in other DDR genes. The combined use of both drugs increased p-chk1 and p-p53 proteins, along with apoptosis signaling. Additionally, venadaparib alone did not induce cell toxicity but significantly increased apoptosis when combined with irinotecan, even at very low concentrations. Conclusions: The combination of a PARPi with irinotecan significantly inhibited cell growth more than the use of either agent alone. Our findings indicate that clinical trials are warranted to confirm the effectiveness of combining PARPi with irinotecan in patients with SCLC. IC50 values of PARP inhibitors in SCLC cells w/or w/o irinotecan 50 Nm IC50 (nM) Olaparib Talazoparib Venadaparib BRCA or PTEN status Irinotecan 50 nM - + - + - + BRCA1 deletion NCI-H1694 5, 933 148. 9 52. 38 2. 19 10, 000 1. 02 BRCA2 deletion NCI-H211 392. 8 37. 20 2. 28 0. 99 3. 82 0. 94 BRCA2 deletion NCI-H1048 1, 704 282. 7 9. 74 2. 36 62. 01 3. 02 PTEN deletion NCI-H1341 10, 000 6, 880 452. 9 83. 9 10, 000 10, 000 PTEN deletion DMS 79 2, 382 221. 9 18. 55 3. 4 175. 16 3. 07 no mutation NCI-H841 5, 099 6, 202 529. 5 380. 5 10, 000 10, 000 no mutation NCI-H2029 10, 000 10, 000 478. 2 56. 16 10, 000 10, 000 no mutation NCI-H2227 3, 407 827. 5 52. 03 2. 17 10, 000 0. 69 no mutation NCI-H146 5, 094 3. 31 56. 11 0. 86 1, 295 0. 93 no mutation NCI-H209 579. 2 0. 05 5. 24 0. 05 8. 18 0. 04 Citation Format: Songji Oh, Miso Kim, Soyeon Kim, Bhumsuk Keam, Jeonghwan Youk, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo. The synergistic potential of PARP inhibitors and irinotecan in small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4531.