Abstract Novel therapeutic agents capable of restoring the function of key tumor suppressors, frequently inactivated across a wide spectrum of cancers, represent a powerful strategy to address the limitations of current treatments and mitigate resistance to existing therapies. Using colorectal cancer (CRC) as a primary indication, we developed an orally bioavailable small-molecule agent, PMG-A9, that restores the activity of a key tumor suppressor and suppresses the oncogenic transcription factor FoxM1, a major driver of therapeutic resistance. Notably, 5-fluorouracil (5-FU), a widely used first-line CRC therapy, is known to induce substantial upregulation of FoxM1. In this study, we demonstrate that PMG-A9 induces a robust, dose-dependent reduction of 5-FU-driven FoxM1 expression in colorectal cancer cells. Exposure of 5-FU-treated cells to PMG-A9 promotes apoptosis through pro-apoptotic mediators, including PUMA. In preclinical CRC xenograft models, PMG-A9 exhibits robust single-agent antitumor efficacy and shows pronounced synergy when combined with multiple chemotherapeutic agents, including 5-FU, while effectively downregulating FoxM1 in vivo. These findings highlight tumor-suppressor reactivation as a promising, broadly applicable therapeutic strategy to improve treatment outcomes for CRC and, potentially, overcome drug resistance across diverse tumor types. Citation Format: Hee-Sung Park, Chakrapani Subramanyam, Kyu-kwang Cho, Se Hee Hyun, Yeonjee Kahm. A first-in-class orally bioavailable small molecule tumor suppressor activator for the treatment of a wide range of cancers 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 3058.
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