PSKH1: A Promising Therapeutic Target in Prostate Cancer, Mechanisms and Potential Interventions

Cancer of the prostate is an important issue on a global scale, and therefore the identification of targets to support the development of therapy for this cancer should be a priority, particularly given the rise in cases of advanced prostate cancer and of patients who have developed resistance to the current standard of care therapies. Protein kinases have been the most heavily researched and targeted class of drug candidates in oncology, and they play a pivotal role in cellular signaling. This review examines Protein Serine Kinase H1 (PSKH1), which is an example of a member of the ‘dark kinome’ that is not extensively studied. PSKH1 recently emerged as a major component of cancer development. Functional RNAi screens demonstrated that PSKH1 enhances proliferation in both androgen-dependent and castration-resistant prostate cancer models. PSKH1's mechanism of action is distinct, as it has two major regulatory nodes: Calcium-dependent phosphorylation by Calmodulin activates it, and Reticulocalbin-3 inhibits PSKH1 through protein-protein interactions. Additionally, PSKH1 activates several pro-survivals signaling pathways (such as p38 MAPK) and regulates alternative splicing of pre-mRNAs in cancer. This review will summarize recent studies relating to the importance of PSKH1 as a potential therapeutic target for prostate cancer. This study discusses PSKH1's general biochemistry, its association with cancer, and the signaling pathways it regulates. Moreover, this study presents a multi-pronged approach linking how it can be inhibited therapeutically, including ATP-competitive and allosteric inhibition, protein- protein interaction displacement, protein degraders (PROTACs), and nucleic acid therapeutics. This study proposes that PSKH1 inhibition represents a novel treatment opportunity to simultaneously interfere with multiple oncogenic pathways and is expected to circumvent resistance and potentiate other treatments. Lastly, this study presents a roadmap of future studies to clinically validate PSKH1 and fast-track the discovery of first-in-class inhibitors of this novel target.