TGF-β receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer.

The Prostate
Channing PallerNatasha Kyprianou

Abstract

Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-β (TGF-β) signaling. We previously demonstrated that aberrant TGF-β signaling accelerates prostate tumor progression in a transgenic mouse model of prostate cancer via effects on epithelial-mesenchymal transition (EMT), driving castration-resistant prostate cancer (CRPC). This study examined the antitumor effect of the combination of TGF-β receptor I (TβRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFβRII male mice were treated with either galunisertib and enzalutamide, in combination or as single agents in three "mini"-trials and the effects on tumor growth, phenotypic EMT, and actin cytoskeleton were evaluated. Galunisertib in combination with enzalutamide significantly suppressed prostate tumor growth, by increasing apoptosis and decreasing cell proliferation of tumor cell populations compared to the inhibitor as a monotherapy (P < 0.05). The combination treatment dramatically reduced cofilin levels, actin cytoskeleton regulator, compared to single agents. Treatment with galunisertib targeted nuclear Smad4 protein (intracellular ...Continue Reading

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Citations

May 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Joshi J AlumkalZheng Xia
Jun 30, 2019·Cell Biology and Toxicology·Clara H LeeRussell S Taichman
Sep 23, 2020·Cancers·Debolina GangulyMatteo Ligorio
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Oct 21, 2020·Cancers·Maddison ArcherNatasha Kyprianou
Feb 8, 2021·Endocrinology·Maddison Archer, Natasha Kyprianou
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Jul 24, 2021·Nature Reviews. Urology·Gaelle FiardMark Emberton

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