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