TRPM4 Expression Predicts Acetalax Sensitivity in Prostate Cancer

Background: Advanced and treatment-refractory prostate cancer, including castration-resistant disease, highlights the need for new therapeutic strategies exploiting targetable vulnerabilities. TRPM4, a calcium-activated monovalent cation channel, regulates cell volume and promotes cancer progression. Our research showed that Acetalax induces selective oncosis-like cell death in TRPM4-positive triple-negative breast cancer, suggesting TRPM4-dependent susceptibility. Targeting TRPM4 may offer advantages over existing therapies by disrupting ion-transport and volume-regulatory mechanisms not addressed by current treatments. We examined TRPM4 expression and Acetalax activity in prostate cancer. Methods: We assessed Acetalax sensitivity in prostate cancer cell lines with high or low TRPM4, including androgen-dependent (LNCaP) and castration-resistant models (PC3, DU145, 22Rv1). TRPM4 dynamics, cellular swelling, and oncosis-associated phenotypes were evaluated by Western blotting and immunofluorescence. Resistant clones were developed by continuous drug exposure. TRPM4 expression in patient samples was analyzed using tissue microarrays (TMAs) and TCGA. Transcriptomic changes following TRPM4 loss were examined by RNA sequencing. Antitumor activity and tolerability were tested in TRPM4-positive PDX models. Results: TRPM4-high prostate cancer cells exhibited rapid swelling, membrane blebbing, and TRPM4 degradation after Acetalax, whereas TRPM4-low cells and resistant clones lacking TRPM4 were unaffected. Resistant clones showed TRPM4 depletion, confirming TRPM4 is required for responsiveness. In patient samples, TRPM4 protein was higher in adenocarcinoma than benign hyperplasia, and TCGA datasets confirmed increased TRPM4 transcripts in tumors relative to normal tissue, with minimal differences across stage or Gleason grade. Transcriptomic profiling revealed gene-expression changes associated with TRPM4 loss, including alterations in ion transport, cytoskeletal organization, and cell-death-related pathways, with a shift toward proliferative programs and reduced stress and inflammatory signaling consistent with disrupted volume-regulatory networks. In vivo, Acetalax significantly suppressed growth of TRPM4-positive PDX tumors in a dose-dependent manner without systemic toxicity. Conclusions: TRPM4 functions as a target and predictive biomarker for Acetalax response in prostate cancer. These findings highlight a TRPM4-dependent therapeutic vulnerability and support biomarker-guided development of Acetalax for TRPM4-expressing, treatment-refractory prostate cancer, including CRPC. Citation Format: Yuka Hoshi, William C. Reinhold, Daiki Taniyama, Yoshitaka Inoue, Augustin Luna, Suresh Kumar, NAI-YUN SUN, Yoo Sun Kim, Yin Juanjuan, Nitin Roper, Adam G. Sowalsky, Naoko Takebe, Yves Pommier. TRPM4 expression predicts Acetalax sensitivity in prostate 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 7717.