An oral first-in-class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer.

Autor: Ushijima M; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Shiota M; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Matsumoto T; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Kashiwagi E; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Inokuchi J; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan., Eto M; Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2022 May; Vol. 113 (5), pp. 1731-1738. Date of Electronic Publication: 2022 Apr 01.
DOI: 10.1111/cas.15280
Abstrakt: Ribosomal S6 kinase has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer through its regulation of YB-1/androgen receptor (AR) signaling. PMD-026, an oral first-in-class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD-026 on YB-1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. Castration-resistant prostate cancer 22Rv1 cells that express high-level AR variants were used in this study. The effect of PMD-026 on YB-1/AR signaling was investigated by quantitative real-time PCR and western blot analysis. The effects of PMD-026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. PMD-026 decreased YB-1 phosphorylation as well as AR V7 mRNA and AR variant expressions in 22Rv1 cells. PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. In a mouse xenograft model, PMD-026 suppressed tumor growth, and the combination of PMD-026 and enzalutamide inhibited tumor growth more prominently than single treatments. Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD-026 and the combination effect with the antiandrogen enzalutamide in castration-resistant prostate cancer. These findings warrant a clinical trial of PMD-026 in prostate cancer patients.
(© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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