Clinical data investigation identifies MARK3 as an oncogenic driver in castration-resistant prostate cancer

Abstract

Castration-resistant prostate cancer (CRPC) represents an aggressive and fatal form of prostate cancer that emerges following resistance to androgen deprivation therapy. Despite the availability of various drugs that can enhance the quality and prolong the survival of CRPC patients, resistance to these therapies is frequently observed, making the disease increasingly difficult to treat. Altered expression of kinases and phosphatases is a critical driver of CRPC and presents a potential target for more effective treatments. In this study, we have performed comprehensive transcriptomic analysis of ∼359 normal and CRPC patient samples from The Cancer Genome Atlas to identify the differentially expressed kinases and phosphatases in patient samples. We shortlisted the candidate genes based on their differential expression profiles, associations with patient survival, Gleason scores, and their impact on the fitness of prostate cancer cell lines. Our in-silico analysis identified microtubule affinity-regulating kinase 3 (MARK3) as a novel CRPC driver that is upregulated in CRPC patients, linked with poor survival outcomes, and affects the fitness of CRPC cells. Furthermore, we found that pharmacological inhibition of MARK3 using PCC0208017, a MARK3 inhibitor, leads to reduced cell viability, migration potential, and cell cycle arrest in the G1 phase in prostate cancer cells. Additionally, RNA sequencing analysis in 22Rv1 cells treated with the MARK3 inhibitor revealed that MARK3 influences genes involved in androgen response, epithelial-mesenchymal transition, mTOR, and myc-signalling, underscoring its pivotal role in CRPC progression. Taken together, our results establish MARK3 as a novel and promising therapeutic target in CRPC.