Targeting AR variant–coactivator interactions to exploit prostate cancer vulnerabilities

Fiorella Magani, Stephanie O. Peacock, Meghan A. Rice, Maria J. Martinez, Ann M. Greene, Pablo S. Magani, Rolando Lyles, Jonathan R. Weitz, Kerry L Burnstein

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Castration-resistant prostate cancer (CRPC) progresses rapidly and is incurable. Constitutively active androgen receptor splice variants (AR-Vs) represent a well-established mechanism of therapeutic resistance and disease progression. These variants lack the AR ligand-binding domain and, as such, are not inhibited by androgen deprivation therapy (ADT), which is the standard systemic approach for advanced prostate cancer. Signaling by AR-Vs, including the clinically relevant AR-V7, is augmented by Vav3, an established AR coactivator in CRPC. Using mutational and biochemical studies, we demonstrated that the Vav3 Diffuse B-cell lymphoma homology (DH) domain interacted with the N-terminal region of AR-V7 (and full length AR). Expression of the Vav3 DH domain disrupted Vav3 interaction with and enhancement of AR-V7 activity. The Vav3 DH domain also disrupted AR-V7 interaction with other AR coactivators: Src1 and Vav2, which are overexpressed in PC. This Vav3 domain was used in proof-of-concept studies to evaluate the effects of disrupting the interaction between AR-V7 and its coactivators on CRPC cells. This disruption decreased CRPC cell proliferation and anchorage-independent growth, caused increased apoptosis, decreased migration, and resulted in the acquisition of morphological changes associated with a less aggressive phenotype. While disrupting the interaction between FL-AR and its coactivators decreased N-C terminal interaction, disrupting the interaction of AR-V7 with its coactivators decreased AR-V7 nuclear levels.

Original languageEnglish (US)
Pages (from-to)1469-1480
Number of pages12
JournalMolecular Cancer Research
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2017

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ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Magani, F., Peacock, S. O., Rice, M. A., Martinez, M. J., Greene, A. M., Magani, P. S., Lyles, R., Weitz, J. R., & Burnstein, K. L. (2017). Targeting AR variant–coactivator interactions to exploit prostate cancer vulnerabilities. Molecular Cancer Research, 15(11), 1469-1480. https://doi.org/10.1158/1541-7786.MCR-17-0280