AR plays a paramount role in the onset and progression of prostate cancer (PC). A majority of the PC patients progress to a lethal stage of the disease, referred to as the metastatic Castration Resistant Prostate Cancer (mCRPC). CRPC remains an incurable malignancy with limited treatment options. 

Need to venture beyond Anti-Androgen Therapies

Reliance of CRPCs on AR despite androgen-depletion, has led to development of AR antagonists, Enzalutamide & Abiraterone. Unfortunately, in spite of early response, most patients relapsed within 2 years, exhibiting renewed AR activity.   

ACK1, a new target in CRPCs

ACK1 is upregulated in ~40% of prostate adenocarcinomas. Importantly, 10 out of 13 CRPCs exhibited ACK1 overexpression. Further, LNCaP cells that are poorly tumorigenic in castrated mice, formed robust CRPC tumors following expression of activated ACK1. The patients that display moderate to strong staining of activated ACK1 have poor prognosis.

ACK1, a histone kinase

We uncovered that ACK1 interacts with AR and deposit novel epigenetic marks, histone H4 Tyr88-phosphorylation. Inhibition of ACK1 by (R)-9b suppressed AR & AR-V7 transcription, inhibiting proliferation of enzalutamide-resistant CRPC tumors.

  • Mahajan K, Malla P, Lawrence H, Chen Z, Sinha CK, Malik R, Shukla S, Kim J, Coppola D, Lawrence N and Mahajan NP*. ACK1 regulates histone Tyr-phosphorylation and AR gene expression in castration resistant prostate cancer. Cancer Cell  2017. Pubmed ID:  28609657
(Top) Prostate TMA stained with AR antibody. (Bottom) Boxplot summarize distributions of staining intensity for AR in prostate biopsies

ACK1 phosphorylates histone H4 at Y88 upstream of the AR transcription start site, leading to theWDR5/MLL2 complex mediated increase of AR transcription. Inhibition of ACK1 reverses the pY88-H4 marks and reduces AR and AR-V7 levels to mitigate castration-resistant prostate tumor growth.