Ack1-mediated Androgen Receptor Phosphorylation Modulates Radiation Resistance in Castration-resistant Prostate Cancer

Androgen deprivation therapy has been the standard of care in prostate cancer due to its effectiveness in initial stages. However, the disease recurs, and this recurrent cancer is referred to as castration-resistant prostate cancer (CRPC). Radiotherapy is the treatment of choice; however, in addition to androgen independence, CRPC is often resistant to radiotherapy, making radioresistant CRPC an incurable disease. The molecular mechanisms by which CRPC cells acquire radioresistance are unclear. Androgen receptor (AR)-tyrosine 267 phosphorylation by Ack1 tyrosine kinase (also known as TNK2) has emerged as an important mechanism of CRPC growth. Here, we demonstrate that pTyr267-AR is recruited to the ATM (ataxia telangiectasia mutated) enhancer in an Ack1-dependent manner to up-regulate ATM expression. Mice engineered to express activated Ack1 exhibited a significant increase in pTyr267-AR and ATM levels. Furthermore, primary human CRPCs with up-regulated activated Ack1 and pTyr267-AR also exhibited significant increase in ATM expression. The Ack1 inhibitor AIM-100 not only inhibited Ack1 activity but also was able to suppress AR Tyr267 phosphorylation and its recruitment to the ATM enhancer. Notably, AIM-100 suppressed Ack1 mediated ATM expression and mitigated the growth of radioresistant CRPC tumors. Thus, our study uncovers a previously unknown mechanism of radioresistance in CRPC, which can be therapeutically reversed by a new synergistic approach that includes radiotherapy along with the suppression of Ack1/AR/ATM signaling by the Ack1 inhibitor, AIM-100. The molecular mechanisms of acquisition of radioresistance in CRPC are not fully understood. Ack1/AR signaling modulates ATM expression to promote radioresistance. Ack1/AR signaling plays a critical role in acquisition of radioresistance in CRPC by modulating the DNA damage response pathways. Ack1/AR signaling represents a new paradigm of radioresistance in CRPC that can be targeted with AIM-100.