Targeting AR Variant–Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities

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 PC. 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. Implications This study demonstrates the potential therapeutic utility of inhibiting constitutively active AR-V signaling by disrupting coactivator binding. Such an approach is significant, as AR-Vs are emerging as important drivers of CRPC that are particularly recalcitrant to current therapies.

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…OIP5 (Opa interacting protein 5) is a cancer testis antigen and has been reported in other cancer types as a type of tumor‐associated antigen (TAA) (Tarnowski et al ., 2016); its detection in PC here suggests OIP5 being a TAA for PC. The remaining four genes VAV2 (VAV guanine nucleotide exchange factor 2), ASNS (asparagine synthesis), DNMT3B (DNA methyltransferase 3 beta), and AURKA (Aurora kinase A) not only all promote PC pathogenesis but also play a role in the development of CRPC (Gravina et al ., 2011; Magani et al ., 2017; Mosquera et al ., 2013; Sircar et al ., 2012). VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012).…”

“…The remaining four genes VAV2 (VAV guanine nucleotide exchange factor 2), ASNS (asparagine synthesis), DNMT3B (DNA methyltransferase 3 beta), and AURKA (Aurora kinase A) not only all promote PC pathogenesis but also play a role in the development of CRPC (Gravina et al ., 2011; Magani et al ., 2017; Mosquera et al ., 2013; Sircar et al ., 2012). VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012). AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013).…”

“…Considering the TCGA cohort had 10 total mortality, it is intriguing that 8 of these 10 deaths occurred in patients with SigMuc1NW‐positive PC (Fig. 2B, P  = 0.00212), which are consistent with VAV2, ASNS, DNMT3B, and AURKA being factors promoting CRPC development (Gravina et al ., 2011; Magani et al ., 2017; Mosquera et al ., 2013; Sircar et al ., 2012). As expected, SigMuc1NW displays an overlapping pattern with the 9‐gene genomic signature used to select DEGs (Fig.…”

Therapies Targeted to Androgen Receptor Signaling Axis in Prostate Cancer: Progress, Challenges, and Hope

“…Interaction of an AR coactivator Vav3 with AR-V7 is suggested to be a mechanism for CRPC where it promotes the ligand-independent transcriptional activity of AR-V7 [179,180]. Accordingly, disruption of this interaction is shown to suppress the proliferation and aggressive phenotype of CRPC cells [181]. Another AR variant coactivator is DBC1 protein, which directly interacts with AR-V7, and its inhibition results in AR-V7 degradation and reduced tumor growth [182].…”

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer

“…An alternative approach to impede the activity of ARfl and the splice variants is to inhibit their interaction with coactivators, many of which are highly expressed in CRPC. Cofactors such as Vav3 and the p160 coactivators have been reported to bind the AR N-terminal AF1 and to control ARfl and ARV7 activities (Nakka et al 2013, Magani et al 2017. However, it is unclear what enables the interaction of these coactivators with the intrinsically disordered N-terminal AF1.…”