TRPM4 Expression as a Predictive Biomarker and a Mechanistic Driver of Acetalax Activity in Prostate Cancer: Preclinical Efficacy Studies.

Advanced and treatment-refractory prostate cancer, including castration-resistant disease, requires new therapeutic strategies. Transient receptor potential melastatin 4 (TRPM4), a calcium-activated monovalent cation channel, regulates cell volume and promotes cancer progression. Acetalax induces oncosis-like death in TRPM4-positive triple-negative breast cancers, suggesting a TRPM4-dependent vulnerability. In this study, we investigated whether TRPM4 expression defines Acetalax sensitivity in prostate cancer. We compared Acetalax sensitivity in TRPM4-high and -low prostate cancer cell lines, including androgen-dependent (LNCaP), castration-resistant (22Rv1), and androgen-independent (PC3 and DU145) models. We evaluated TRPM4 dynamics and oncosis-associated phenotypes using Western blotting and immunofluorescence. Resistant clones were developed through continuous drug exposure. TRPM4 expression in patient samples was analyzed using prostate cancer tissue microarray and The Cancer Genome Atlas. Transcriptional changes following TRPM4 loss were examined by RNA sequencing (RNA-seq). Antitumor activity and tolerability were evaluated in TRPM4-positive patient-derived xenograft (PDX) models. TRPM4-high cells (PC3, LNCaP, and 22Rv1) underwent oncosis-like swelling and TRPM4 degradation upon Acetalax exposure, whereas TRPM4-low cell and resistant clones (DU145 and chronic exposure cells) remained insensitive and lacked TRPM4 expression. RNA-seq revealed transcriptomic remodeling associated with TRPM4 loss. TRPM4 was significantly increased in tumors compared with normal tissues and was unchanged across stages or Gleason scores. In TRPM4-positive PDX models, Acetalax (300 mg/kg) significantly suppressed tumor growth without body weight loss, indicating antitumor efficacy without overt toxicity. TRPM4 is a mechanistic driver and predictive biomarker of Acetalax response in prostate cancer, supporting TRPM4-dependent targeting and providing a rationale for the clinical development of Acetalax for TRPM4-expressing and treatment-refractory prostate cancer.