Abstract 4550: Synergistic combinations of lurbinectedin with ONC212 in pancreatic cancer

Abstract Pancreatic cancer is a devastating disease with a poor five-year survival rate of approximately 12%. Given the poor prognosis of the disease, there is urgent need for novel therapeutic regimens. Lurbinectedin is chemotherapeutic compound that stalls and degrades RNA Polymerase II after binding to guanine-rich sequences in the minor groove of DNA. This stalls transcription machinery and leads to single- and double- stranded breaks in DNA and subsequent apoptosis. Our group recently described lurbinectedin’s potency as both a single agent and combinatorial agent with irinotecan and 5-fluorouracil in pancreatic cancer cell lines. We also recently discovered a synergistic interaction between lurbinectedin and ONC201/TIC10, a novel compound that induces the TRAIL apoptotic pathway, in small cell lung cancer cell lines. Synergy was accompanied by an activation of p-Chk1 and the integrated stress response. We now demonstrate a synergistic combination of lurbinectedin and ONC212, an imipridone and chemical derivative of ONC201, results in highly efficient killing of pancreatic tumor cells at sub-nanomolar concentrations of lurbinectedin and sub-micromolar concentrations of ONC212. We hypothesize that the integrated stress response underlies lurbinectedin and ONC212 synergy. We further hypothesize a combination of lurbinectedin and ONC212 will sensitize the tumor cells to CD8+ T-cell killing, which will be examined via co-culture assays. Our results are developing insights into a novel combinatorial therapeutic regimen while investigating the molecular mechanisms underlying synergism. Citation Format: Tej Tummala, Ashley S. Sevilla Uruchurtu, Nicholas R. Liguori, E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Synergistic combinations of lurbinectedin with ONC212 in pancreatic 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 4550.