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

Channing Paller, H. Pu, Diane E. Begemann, Cameron A. Wade, Patrick J. Hensley, Natasha Kyprianou

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: 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). Methods: 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. 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-β effector), but had no effect on nuclear AR. Consequential to TGF-β inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-β1 ligand, in response to galunisertib, was blocked by enzalutamide. Conclusion: Our results provide novel insights into the therapeutic value of targeting TGF-β 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-β blockade and antiandrogens to optimize therapeutic response in CRPC.

Original languageEnglish
JournalProstate
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

LY-2157299
Growth Factor Receptors
Transforming Growth Factors
Prostatic Neoplasms
Epithelial-Mesenchymal Transition
Prostate
Androgen Antagonists
Neoplasms
Castration
Androgen Receptors
Actin Cytoskeleton
Smad4 Protein
Actin Depolymerizing Factors
MDV 3100
Cytoplasmic and Nuclear Receptors
Growth
Nuclear Proteins
Cytoskeleton
Transgenic Mice
Cell Proliferation

Keywords

  • EMT
  • enzalutamide
  • TGF-β inhibition strong
  • therapeutic response

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

TGF-β receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer. / Paller, Channing; Pu, H.; Begemann, Diane E.; Wade, Cameron A.; Hensley, Patrick J.; Kyprianou, Natasha.

In: Prostate, 01.01.2018.

Research output: Contribution to journalArticle

Paller, Channing ; Pu, H. ; Begemann, Diane E. ; Wade, Cameron A. ; Hensley, Patrick J. ; Kyprianou, Natasha. / TGF-β receptor I inhibitor enhances response to enzalutamide in a pre-clinical model of advanced prostate cancer. In: Prostate. 2018.
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AB - Background: 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). Methods: 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. 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-β effector), but had no effect on nuclear AR. Consequential to TGF-β inhibition there was an EMT reversion to mesenchymal-epithelial transition (MET) and re-differentiation of prostate tumors. Elevated intratumoral TGF-β1 ligand, in response to galunisertib, was blocked by enzalutamide. Conclusion: Our results provide novel insights into the therapeutic value of targeting TGF-β 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-β blockade and antiandrogens to optimize therapeutic response in CRPC.

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