Canagliflozin is a novel androgen receptor pathway inhibitor for castrate-sensitive and castrate-resistant prostate cancer

Amr Ali; Fiorella Di Pastena; Olga-Demetra Biziotis; Simon Wang; Evangelia E Tsakiridis; Daniel Del Rosso; James C Fredenburgh; Jeffrey I Weitz; Sebastien J Hotte; Jonathan L Bramson; Gregory R Steinberg; Theodoros Tsakiridis

doi:10.1016/j.canlet.2026.218535

Canagliflozin is a novel androgen receptor pathway inhibitor for castrate-sensitive and castrate-resistant prostate cancer

Cancer Lett. 2026 Aug 1:652:218535. doi: 10.1016/j.canlet.2026.218535. Epub 2026 Apr 24.

Affiliations

¹ Department of Oncology, McMaster University, Hamilton, ON, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
² Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
³ Department of Oncology, McMaster University, Hamilton, ON, Canada.
⁴ Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁵ Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
⁶ Department of Oncology, McMaster University, Hamilton, ON, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
⁷ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
⁸ Department of Oncology, McMaster University, Hamilton, ON, Canada; Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, ON, Canada; Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada; Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON, Canada; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. Electronic address: tsakirt@mcmaster.ca.

PMID: 42036010
DOI: 10.1016/j.canlet.2026.218535

Abstract

Androgen receptor (AR) pathway inhibitors (ARPIs) improve outcomes in advanced prostate cancer (PC) in combination with androgen deprivation therapy (ADT). However, PC rapidly develops ARPI resistance, frequently through expression of truncated AR variants (AR-Vs), like AR-V7, highlighting a need for more effective therapies. The sodium-glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin, an approved diabetes drug, also suppresses PC growth and inhibits AR-related gene expression. Therefore, we hypothesized that canagliflozin may directly inhibit AR. Cellular and tumor models of PC were subjected to proliferation, clonogenic, and xenograft studies. RNA-seq and siRNA knockdown approaches defined molecular mechanisms. Molecular docking, thermal shift, and surface plasmon resonance assays assessed drug-target interactions. Stable sh-AR full-length (sh-AR-FL) and sh-AR-V7 cell lines were generated to interrogate the transcriptomic impact of AR and prognostic analysis was performed using clinical datasets. We found that canagliflozin suppresses PC growth through AR. It interacts with the AR ligand binding domain (LBD) with estimated affinity comparable to ARPIs and blocks AR signaling. Canagliflozin reduces the transcript and protein levels of the HSP70 chaperone and suppresses the cytoplasmic and nuclear levels of AR-FL and AR-Vs through proteasomal degradation. It mediates substantial reprogramming of PC transcriptional activity, including inhibition of AR pathway, cell-cycle, E2F and MYC hallmark targets. Its gene expression profile overlaps with silencing AR-FL or AR-V7 is associated with improved prognosis in clinical datasets. The results of this study demonstrate the potential for canagliflozin to function as a clinically useful ARPI and support prospective clinical investigation of this drug in PC.

Keywords: AR variants (AR-Vs); Androgen receptor (AR); Canagliflozin; Castrate-resistant prostate cancer (CRPC); Castrate-sensitive prostate cancer (CSPC); Sodium-glucose cotransporter 2 inhibitor (SGLT2i).

MeSH terms

Androgen Receptor Antagonists* / pharmacology
Animals
Canagliflozin* / pharmacology
Canagliflozin* / therapeutic use
Cell Line, Tumor
Cell Proliferation / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Humans
Male
Mice
Molecular Docking Simulation
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / metabolism
Prostatic Neoplasms, Castration-Resistant* / pathology
Receptors, Androgen* / chemistry
Receptors, Androgen* / genetics
Receptors, Androgen* / metabolism
Signal Transduction / drug effects
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
Xenograft Model Antitumor Assays

Substances

Canagliflozin
Receptors, Androgen
AR protein, human
Androgen Receptor Antagonists
Sodium-Glucose Transporter 2 Inhibitors