Abstract 7212: Preclinical analysis of ONC206 and ONC212 with lurbinectedin 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, it is vital to develop novel improved therapeutic regimens. Lurbinectedin is a chemotherapeutic that stalls and degrades RNA Polymerase II after binding to guanine-rich sequences in the minor groove of DNA, stalling transcription and inducing single- and double-stranded DNA breaks. 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. Our group also recently described a synergistic interaction between lurbinectedin and imipridone ONC201/Dordaviprone, an anticancer compound that induces the TRAIL apoptotic pathway, in small cell lung cancer cell lines. We now demonstrate that a combination of lurbinectedin and ONC212, a chemical derivative of ONC201, results in highly efficient and synergistic killing of pancreatic tumor cells in vitro. Under combinatorial conditions, cells seemingly exhibit an upregulation of DR5 and γH2AX and a downregulation of ClpX in the presence of ONC212. Future studies will analyze whether a combination of lurbinectedin and ONC212 or lurbinectedin and ONC206, another imipridone and chemical analogue of ONC201, proves more efficient at killing pancreatic tumor cells in vitro. Our results are developing insights into novel combinatorial therapeutic regimens while investigating the molecular mechanisms underlying synergism. Citation Format: Tej Tummala, Ashley S. Uruchurtu, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Preclinical analysis of ONC206 and ONC212 with lurbinectedin in pancreatic cancer [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 7212.