Abstract 4909: Molecular analysis of small cell lung cancer provides insights into mechanism of action underlying the novel drug combination of lurbinectedin and TIC10/ONC201

Abstract

Abstract We previously explored the combination of novel imipridone TIC10/ONC201 and small molecule RNA polymerase inhibitor lurbinectedin as a potentially effective treatment regimen for small cell lung cancer (SCLC). Data from cell viability experiments demonstrated synergistic killing of SCLC cells with minimal death of healthy control cells. Analysis of intracellular proteins via Western blot indicated that combinatorial treatment induces the integrated stress response, DNA damage/cell cycle checkpoint responses, and increased apoptosis of tumor cells. We have utilized the Luminex 200 platform to perform analyses of cytokine levels in SCLC cell lines with various genetic alterations before and after ONC201 and lurbinectedin treatment. Our results revealed significant changes in cytokine levels following treatment indicating potential immunomodulatory and angioregulatory effects of ONC201 and lurbinectedin. CCL3, known to recruit and activate granulocytes, was found to be elevated by treatment with lurbinectedin, ONC201 and combination versus control. Angiopoietin 1, which contributes to blood vessel maturation, and angiopoietin 2, which promotes neovascularisation, were elevated by all drug treatments in H1882 SCLC cells. Our ongoing studies are further analysing the importance of specific cytokines in tumor vascularity and in recruitment and killing of SCLC cells by immune cells. Results from these experiments are helping to elucidate the molecular mechanisms underlying SCLC, its immune landscape, and treatment response. Citation Format: Ashley Sanchez Sevilla Uruchurtu, Nicholas Liguori, Leiqing Zhang, Kelsey Huntington, Lanlan Zhou, Young Lee, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Molecular analysis of small cell lung cancer provides insights into mechanism of action underlying the novel drug combination of lurbinectedin and TIC10/ONC201. [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 4909.