Imipridones ONC201, ONC206, and ONC212 Show Potent Killing and Colony Arrest of Small-Cell Lung Cancer Cell Lines.

Abstract Introduction: Small cell lung cancer (SCLC) represents about 15% of all lung cancers, with an estimated 5-year survival rate of only 7%. While most SCLC cases initially respond to chemotherapy, a majority (70-80%) of cases recur and become resistant to first-line treatments. As such, further investigation of novel therapeutics is heavily warranted. Imipridones are a class of selective anti-cancer drugs that activate integrated stress response and increase TRAIL expression to lead to cancer cell death. While ONC201 (dordaviprone) has been investigated in small-cell and various other cancers, its derivatives ONC206 and ONC212 have not yet been explored within SCLC. As such, the present study compares ONC201, ONC206, and ONC212 within the context of SCLC. Methods: Three SCLC cell lines were used: H526, H1048, H1882. For viability assays, cells were plated at 1000 cells/well in a 96-well plate and allowed to adhere overnight before treatment. Viability was assessed 72h after imipridone treatment by Cell-TiterGlo® assay to yield each drug’s IC50. Western Blots (WBs) were performed across cell lines at 24h, 48h, and 72h following equitoxic treatments with each imipridone (IC25, IC50, IC75). Colony formation assays (CFAs) were also performed in triplicate for two cell lines (H1048, H1882) after three-day treatment with equitoxic doses of each drug followed by fourteen days of drug-free incubation. Results: Across cell lines, ONC212 exhibited the lowest IC50, followed by ONC206 and ONC201. By WB, changes in ATF4, cPARP, and ClpX differed by drug, with ONC212 generally inducing the earliest and most significant changes in expression. CFA showed that ONC212 resulted in the greatest decrease in colony formation after 72 hours of treatment, followed by ONC206 and then ONC201. Conclusions: The present findings suggest that SCLC may be highly sensitive to imipridones, particularly ONC212. Future works will aim to explore combination therapies and potential mechanisms including senescence induction, cell cycle alterations that may lead to reproductive arrest, metabolic changes, and alterations in growth and survival pathways in order to further characterize sensitivity and the colony arrest phenotype. Citation Format: Audrey Y. Su, Connor Purcell, Shengliang Zhang, Lanlan Zhou, Ashley S. Uruchurtu, Wafik S. El-Deiry. Imipridones ONC201, ONC206, and ONC212 show potent killing and colony arrest of small-cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2937.