Advanced and treatment-refractory prostate cancer, including castration-resistant disease, require new therapeutic strategies. 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. Here, 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, DU145) models. We evaluated TRPM4 dynamics and oncosis-associated phenotypes by 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 (TCGA). 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 elevated in tumors versus 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.
Molecular cancer therapeutics. 2026 Apr 22 [Epub ahead of print]
Yuka Hoshi-Kadonosawa, William C Reinhold, Daiki Taniyama, Yoshitaka Inoue, Augustin Luna, Suresh Kumar, Nai-Yun Sun, Yoo Sun Kim, Juan Juan Yin, Nitin Roper, Adam G Sowalsky, William D Figg, Naoko Takebe, Yves Pommier
National Cancer Institute Bethesda United States., National Cancer Institute Bethesda, MD United States., National Cancer Institute United States., United States National Library of Medicine Bethesda United States., United States National Library of Medicine Bethesda, MD United States., National Cancer Institute Bethesda, Maryland United States., OU Health Stephenson Cancer Center Oklahoma City, Oklahoma United States.