Abstract 4204: A novel triple combination therapy in small cell lung cancer targeting DNA damage repair as a mechanism of resistance

Small cell lung cancer (SCLC) accounts for approximately 15% of new lung cancer cases in the US every year. Treatment options remain limited and 5-year survival rates have languished at around 7% for the past decade. SCLC is notorious for its response to standard etoposide-platinum doublet therapy; initially responsive, it almost always relapses and no longer responds to first-line treatments. The DNA damage response (DDR) has been credibly posited as a targetable mechanism of resistance to DNA-damaging agents. For our experiments, we added prexasertib to our prior combination of imipridone ONC201 (dordaviprone) and small molecule lurbinectedin, previously shown to be synergistic. Prexasertib is a dual inhibitor of Chk1 and 2, protein kinases in the DDR pathway that regulate downstream cell cycle checkpoint (CCC) proteins particularly implicated in G1/S transition and G2 entry. Synergy scores and western blot data from experiments in four cell lines (H1048, H1882, H1105, H1417) point to the role of the DDR-CCC pathway in SCLC treatment resistance and offer a novel treatment modality for testing in vivo, with the ultimate view to progress into the clinic. Citation Format: Ashley Sanchez Sevilla Uruchurtu, Kevin Kwon, Shengliang Zhang, Tyler Roady, Wafik S. El-Deiry. A novel triple combination therapy in small cell lung cancer targeting DNA damage repair as a mechanism of resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4204.