DNA damage repair lies at the core of all cells’ survival strategy, including cancerous. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of multiple kinases. Recent studies on Tousled like Kinases have brought significant clarity on the effectors of these kinases which stands to regulate DSB repair. In addition to their well-established role in the DDR and cell cycle checkpoint mediation after DNA damage or inhibitors of replication, their suspected involvement in the actual DSB repair process has more recently been strengthened by the important finding that TLK1 phosphorylates RAD54 and regulates some of its activities and localization in the cell. Earlier findings of its regulation of RAD9 during checkpoint deactivation as well as defined steps during NHEJ ends processing were earlier hints of its important involvement broadly in DSB repair. All this has opened up new avenues to target cancer cells in combination therapy with genotoxins and TLK inhibitors.

Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas’ associated with poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas’ still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained under-represented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa.

Cellular organisms possess intricate DNA damage repair and tolerance pathways to manage various DNA lesions arising from endogenous or exogenous sources. Dysregulation of these pathways is associated with cancer development and progression. Synthetic lethality (SL), a promising cancer therapy concept, involves exploiting the simultaneous functional loss of two genes for selective cell death. PARP inhibitors (PARPis) have demonstrated success in BRCA-deficient tumors. Cisplatin (CPT), a widely used chemotherapy agent, forms DNA adducts and crosslinks, rendering it effective against various cancers but less so for prostate cancer (PCa) due to resistance and toxicity. Here, we explore the therapeutic potential of TLK1, a kinase upregulated in androgen-insensitive PCa cells, as a target for enhancing CPT-based therapy. TLK1 phosphorylates key homologous recombination repair (HRR) proteins RAD54L and RAD54B, critical for HRR alongside RAD51. The combination of CPT with TLK1 inhibitor J54 exhibits SL in androgen-insensitive PCa cells. The formation of double-strand break intermediates during inter-strand crosslink processing necessitates HRR for effective repair. Therefore, targeting TLK1 with J54 enhances the SL of CPT by impeding HRR, leading to increased sensitivity in PCa cells. These findings suggest a promising approach for improving CPT-based therapies in PCa, particularly in androgen-insensitive cases. By elucidating the role of TLK1 in CPT resistance, this study provides valuable insights into potential therapeutic targets to overcome PCa resistance to CPT chemotherapy. Further investigations into TLK1 inhibition in combination with other DNA-damaging agents may pave the way for more effective and targeted treatments for PCa and other cancers that exhibit resistance to traditional chemotherapy agents.