Androgen receptor (AR)
AR plays a paramount role in the onset and progression of prostate cancer (PC). This very facet underlies androgen deprivation therapy (ADT), a preferred treatment to negate AR transcriptional co-activator activity. While treatment with AR antagonists or orchiectomy provides immediate palliative benefits, these ADTs are ineffective long term, as the recalcitrant disease recurs within 2-3 years. A majority of the PC patients progress to a lethal stage of the disease, referred to as the metastatic Castration Resistant Prostate Cancer (mCRPC). Consequently, resistance to ADT has become one of the most vexing problems in PC therapy and thus, CRPC remains an incurable malignancy with limited treatment options.
Need to venture beyond Anti-Androgen Therapies
CRPC cells rely on AR for their growth despite androgen-depletion. Enzalutamide, a second generation AR antagonist, although efficiently suppressed AR transcriptional activity by overcoming its nuclear translocation, the overall survival advantage was found to be ~6 months, and most patients relapsed within 2 years. Interestingly, these relapsed patients exhibit renewed AR target gene expression. AR-V7 splice variant may be a clinically relevant mechanism for resistance to enzalutamide and androgen-synthesis inhibitor, abiraterone, in CRPC patients. Overall, the relative short-term efficacy of enzalutamide and abiraterone revealed two major caveats, inhibition of AR protein activity is not enough, to achieve complete remission, ablation of AR transcription is the key. However, targeted inhibition of AR and its splice variant, AR-V7 transcription, with small molecule inhibitors has not yet been accomplished.
ACK1 in CRPCs
ACK1 is a structurally unique non-receptor tyrosine kinase that is upregulated in ~25% of prostate adenocarcinomas. Importantly, 10 out of 13 CRPCs exhibited 5- to >100-fold ACK1 overexpression. Further, LNCaP cells that are poorly tumorigenic in castrated mice, formed robust CRPC tumors following expression of activated ACK1. Moreover, expression of activated ACK1 not only correlates positively with the progression of disease to CRPC stage, but also revealed that patients that display moderate to strong staining of activated ACK1 have poor prognosis. Combined, these studies have established a crucial role for ACK1 in prostate cancer pathogenesis.
Serendipitously, we uncovered that ACK1 establish an autonomous epigenetic circuitry.