Abstract 4497: Imofinostat enhances chemotherapy response by targeting HDAC3-NRF2 pathway in KRAS-mutant pancreatic cancer.

Abstract Background: Aberrant HDAC3 activation in solid tumors contributes to therapeutic resistance and poor prognosis. Inhibition of HDAC3 has therefore emerged as a potential strategy to overcome resistance to chemo-, radio-, and immunotherapies. Imofinostat (also known as ABT-301), a hydroxamic acid-based HDAC inhibitor, exhibits potent HDAC class I selectivity with preferential inhibition of HDAC3 (IC50 = 7 nM). This study evaluated the antitumor efficacy of imofinostat, alone or in combination with standard therapies, in cancers exhibiting high HDAC3 dependency. Methods: HDAC3 dependency was assessed across cancer types using the DepMap database. The in vitro anti-proliferation effects of imofinostat, alone or in combination with gemcitabine, were measured via standard cell viability assays across multiple cancer cell lines. RNA sequencing and Western blot analyses were conducted to examine transcriptomic and protein expression changes following imofinostat treatment. In vivo efficacy of imofinostat, alone or in combination with chemotherapies, was evaluated in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) xenograft models. Results: DepMap analysis revealed PDAC, bladder cancer, brain tumors, and leukemia as malignancies with pronounced HDAC3 dependency. In vitro, imofinostat inhibited cell proliferation in PDAC cell lines (GI50 0.3 - 4.8 μM) and bladder cancer cell lines (GI50 0.2 - 0.5 μM), demonstrating synergistic effects with gemcitabine and pemetrexed, respectively. Mechanistically, transcriptomic profiling in PDAC revealed imofinostat downregulated antioxidant genes (NQO1, GPX4, GSS, COQ2) and upregulated ferroptosis-associated genes (STEAP3, FTL, SLC39A14, CP). Consistently, Western blot analysis of KRAS-mutant PDAC xenografts confirmed target engagement (increased histone H3 acetylation) and reduced expression of NRF2 and its targets (NQO1, SLC7A11). Together, these findings indicate that imofinostat suppresses NRF2-driven antioxidant programs, enhances ferroptotic susceptibility and exposes metabolic vulnerabilities linked to oncogenic KRAS. In vivo, imofinostat alone or in combination with gemcitabine significantly inhibited tumor growth in NRF2-high, KRAS-mutant xenograft models. Conclusion: Imofinostat exerts potent anti-tumor activity via HDAC3 inhibition, exploiting the HDAC3-NRF2 vulnerability in KRAS-mutant PDAC models. Its combination with gemcitabine further enhanced efficacy, supporting the clinical potential of imofinostat with DNA-damaging or metabolic agents in NRF2-activated cancers. Citation Format: Yi-Chen Lin, Ka-Po Tse, Chung-Yen Li, Tzu-Hsien Yang, Shih-Han Huang, Sue-Ming Chang, Mark Shiuh-Sheng Horng, John Tsu-An Hsu, Kien Thiam Tan. Imofinostat enhances chemotherapy response by targeting HDAC3-NRF2 pathway in KRAS-mutant pancreatic cancer 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 4497.