Tousled-like kinase 1: a novel factor with multifaceted role in mCRPC progression and development of therapy resistance

Standard treatment for advanced Prostate Cancer (PCa) consists of androgen deprivation therapy (ADT), but ultimately fails, resulting in the incurable phase of the disease: metastatic castration-resistant prostate cancer (mCRPC). Targeting PCa cells before their progression to mCRPC would greatly improve the outcome, if strategies could be devised selectively targeting androgen receptor (AR)-dependent and/or independent compensatory pathways which promote mCRPC development. Combination therapy by targeting the DNA damage response (DDR) along with ADT has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. In recent years, our lab has identified a key role for the DDR kinase, TLK1, in mediating key aspects of adaptation to ADT, first by promoting a cell cycle arrest (through the TLK1>NEK1>ATR>Chk1 kinase cascade) under the unfavorable growth conditions (androgen deprivation), and then by reprogramming the PCa cells to adapt to androgen-independent growth via the NEK1>YAP/AR>CRPC conversion. In addition, TLK1 plays a key anti-apoptotic role via the NEK1>VDAC1 regulation on the intrinsic mitochondrial apoptotic pathway when the DDR is activated. Finally, TLK1 was recently identified as having an important role in motility and metastasis via regulation of the kinases MK5/PRAK and AKT (indirectly via AKTIP).