Targeting Prostate Cancer, the ‘Tousled Way’

Abstract

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 a 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 underrepresented 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.

Autophosphorylation of the Tousled-like kinases TLK1 and TLK2 regulates recruitment to damaged chromatin via PCNA interaction

“…There are ongoing efforts to develop TLK1 and TLK2 inhibitors for targeting cancer cells with their promising roles in maintaining genome stability (64)(65)(66). Emerging evidence demonstrated that TLK1 and TLK2 are involved in cancer progression and therapeutic resistance (67)(68)(69)(70) and it has been shown that inhibition of TLK potentiates cell-killing in different types of cancers (1,(70)(71)(72)(73)(74), making TLK 1 and 2 attractive targets for therapeutic strategy development.…”

Untousling the Role of Tousled-like Kinase 1 in DNA Damage Repair

“…These include, for example: topoisomerase poisons, bleomycin, MMC, PARPis, and cisplatin, all of which ultimately lead to the formation of SSBs and DSBs. For some of these (e.g., doxorubicin and cisplatin), direct evidence of synthetic lethality in combination with TLK inhibitors has already been verified [38,61]. Of particular note is the reported synthetic lethal interaction of combining the knock down of TLKs with PARP inhibitors [36], which could be expected to engender a double hit on both NHEJ and HRR based on the already described functions of TLKs.…”

A Comprehensive Review and Androgen Deprivation Therapy and Its Impact on Alzheimer’s Disease Risk in Older Men with Prostate Cancer

“…15 Recent studies have revealed a probable link between PCa, AD, and ADT, enticing further research into the underlying mechanisms and clinical implications. 17 ADT, a conventional treatment strategy in advanced PCa, seeks to decrease androgen signalling, hence preventing tumour development and progression. However, research studies suggest that extended ADT might have unforeseen consequences for cognitive function, possibly exposing people to neurodegenerative illnesses like AD.…”

“… 15 Recent studies have revealed a probable link between PCa, AD, and ADT, enticing further research into the underlying mechanisms and clinical implications. 17 …”