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

ABSTRACT: Acetalax, a repurposed ion‐transport–targeting compound, induces rapid oncosis-like cell death selectively in TRPM4-expressing cancer cells. Here, we investigated TRPM4 as a mechanistic driver and predictive biomarker of Acetalax response in prostate cancer. Across prostate cancer cell lines, TRPM4-high cells (PC3, LNCaP, 22Rv1) exhibited Acetalax sensitivity, cell swelling, nuclear enlargement, membrane blebbing, and proteasome-dependent TRPM4 degradation, whereas TRPM4-low DU145 cells were resistant. Chronic Acetalax exposure generated resistant clones characterized by complete loss of TRPM4 expression. RNA sequencing of parental and resistant cells identified TRPM4 loss–associated transcriptomic remodeling, including upregulation of proliferative programs and suppression of inflammatory and stress-response pathways. In TRPM4-positive prostate cancer patient-derived xenograft (PDX) models (LuCaP147 and LuCaP167), Acetalax significantly suppressed tumor growth without inducing body-weight loss. TRPM4 expression was consistently elevated in prostate tumors relative to benign tissues and remained high across disease stages and Gleason grades. Together, these results define TRPM4 as a mechanistic determinant of Acetalax sensitivity and provide a rationale for TRPM4-based patient stratification and the development of Acetalax for treatment-refractory prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313554 | GEO | 2026/06/22

REPOSITORIES: GEO

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