Abstract
Abstract Small cell lung cancer (SCLC) remains a significant clinical concern, with only a 7% 5 year survival rate; therefore, there remains an unmet need for efficacious treatments. Lurbinectedin was FDA approved in 2019 to treat platinum-resistant SCLC. Preliminary experiments in SCLC cell lines indicated an increase in intracellular pChk1 when treated with lurbinectedin. Based on these data and our understanding of the role of checkpoint kinases in the DNA damage response (DDR), we hypothesize that the activity of Chk1 is indicative of upregulated DDR activity as a result of double stranded breaks and replicative stress induced by lurbinectedin. In subsequent experiments, we sought to identify the role of Chk1 and Chk2 in the tumor cell response to lurbinectedin by inhibiting their activity using prexasertib (LY2606368, Acrivon Therapeutics). Cell viability experiments indicate decreased tumor cell viability when three SCLC cell lines (H1048, H1105, H1417) are treated with prexasertib as a single agent and in combination with lurbinectedin. Western blot analysis of intracellular proteins from the same SCLC cell lines treated with both drugs demonstrate dose-dependent effects on cell death marker cPARP, DNA damage marker γH2AX, and DDR/cell cycle pathway kinases cdk1 and 2. Ongoing experiments seek to replicate results using alternative Chk1/2 inhibitors, and to explore the effect of lurbinectedin-Chk1/2 inhibitor combination treatment on antitumor immune effector function by in vitro co-culture. Citation Format: Ashley Sanchez Sevilla Uruchurtu, Tyler Roady, Agenxnie Anderson, Wafik S. El-Deiry. Chk1/2 inhibition enhances response to lurbinectedin treatment 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(6_Suppl):Abstract nr 3191.
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