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

BACKGROUND: Prostate cancer progression is navigated by the androgen receptor (AR) and transforming-growth factor-ß (TGF-ß) signaling. We previously demonstrated that aberrant TGF-ß 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). METHODS: This study examined the antitumor effect of the combination of TGF-ß receptor I (TßRI) inhibitor, galunisertib, and FDA-approved antiandrogen enzalutamide, in our pre-clinical model. Age-matched genotypically characterized DNTGFßRII 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. RESULTS: 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 TGF-ß effector), but had no effect on nuclear AR. Consequential to TGF-ß inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-ß1 ligand, in response to galunisertib, was blocked by enzalutamide. CONCLUSION: Our results provide novel insights into the therapeutic value of targeting TGF-ß signaling to overcome resistance to enzalutamide in prostate cancer by phenotypic reprogramming of EMT towards tumor re-differentiation and cytoskeleton remodeling. This translational work is significant in sequencing TGF-ß blockade and antiandrogens to optimize therapeutic response in CRPC.

Aberrant TGF-ß Signaling Drives Castration-Resistant Prostate Cancer in a Male Mouse Model of Prostate Tumorigenesis.

The androgen receptor (AR) plays a critical role as a driver of castration-resistant prostate cancer (CRPC). Our previous studies demonstrated that disruption of transforming growth factor-ß (TGF-ß) signaling via introduction of dominant-negative transforming growth factor-ß type II receptor (DNTGFßRII) in the prostate epithelium of transgenic adenocarcinoma of the prostate mice accelerated tumor. This study investigated the consequences of disrupted TGF-ß signaling on prostate tumor growth under conditions of castration-induced androgen deprivation in the preclinical model of DNTGFßRII. Our results indicate that in response to androgen deprivation therapy (ADT) the proliferative index in prostate tumors from DNTGFßRII mice was higher compared with prostate tumors from TGFßRII wild-type (WT) mice, whereas there was a reduced incidence of apoptosis in tumors from DNTGFßRII. Protein and gene expression profiling revealed that tumors from DNTGFßRII mice exhibit a strong nuclear AR localization among the prostate tumor epithelial cells and increased AR messenger RNA after ADT. In contrast, TGFßRII WT mice exhibited a marked loss in nuclear AR in prostate tumor acini (20 weeks), followed by a downregulation of AR and transmembrane protease serine 2 messenger RNA. There was a significant increase in nuclear AR and activity in prostate tumors from castrate DNTGFßRII compared with TGFßRII WT mice. Consequential to aberrant TGF-ß signaling, ADT enhanced expression and nuclear localization of Smad4 and ß-catenin. Our findings support that under castrate conditions, aberrant TGF-ß signaling leads to AR activation and ß-catenin nuclear localization, an adaptation mechanism contributing to emergence of CRPC. The work defines a potentially significant new targeting platform for overcoming therapeutic resistance in CRPC.