Posted March 27, 2019

Atish Choudhury, M.D., Ph.D., Dana-Farber Cancer Institute

In prostate cancer (PCa), the development of castration resistance is pivotal in the progression to aggressive and lethal disease. However, our understanding of all the pathways involved that lead PCa to develop this resistance is incomplete. Increased understanding of these mechanisms could result in better drug design to target these resistance mechanisms and allow current hormonal treatments to work better and for a longer period of time. Dr. Atish Choudhury at Dana-Farber Cancer Institute sought to shed more light on these pathways of resistance, and identify novel drug targets for castration-resistant prostate cancer (CRPC).

With funding from a FY11 Physician Research Training Award, Dr. Choudhury and his research team started by attempting to identify genes that allow PCa cells to form tumors in a mouse model in the absence of male hormones. This is analogous to what happens in patients when their cancers become resistant to hormonal therapies. They performed a high throughput genetic screen to identify a number of proteins called kinases that enable androgen-dependent prostate epithelial cells to form new tumors under androgen deprived conditions. One of the kinases identified in the screen, NEK6, is a mitotic-related kinase that mediates androgen-independent tumor growth. Dr. Choudhury further characterized the role of this kinase by demonstrating that NEK6 was overexpressed in a subset of human PCas, and that silencing NEK6 in castration resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Additional gene expression profiling studies also showed that NEK6 overexpression stimulated cytoskeletal, differentiation, and immune signaling pathways, and maintained gene expression patterns normally decreased by castration.

Overall, these studies establish NEK6 signaling as a central mechanism mediating CRPC. To continue translating these findings to the clinic, studies demonstrating the clinical relevance of the NEK6 pathway will be needed, and Dr. Choudhury plans to investigate whether PCa tumors from patients that have become resistant to hormonal therapies demonstrate any evidence of over-activity of NEK6 or its downstream pathways that were identified in the previous model system. Confirmation of these findings in patient samples would support the rationale for designing a drug that can specifically target NEK6, evaluate its efficacy in patients where NEK6 appears to be over-active. Dr. Choudhury hopes these findings will ultimately result in new treatment options for men with CRPC.

Immunohistochemical staining at X20 magnification for NEK6 in prostate cancer tissue microarrays. Low- (left and middle) and high-grade (right) cases are represented, each core showing tumor infiltration in between benign glands with higher expression seen in the tumor. H&E, hematoxlyin and eosin

Publication:

Choudhury A, Schinzel A, Cotter MB, et al. 2017. Castration Resistance in Prostate Cancer is Mediated by the Kinase NEK6. Cancer Research. 77(3):753-765.

Link:

Molecular Determinants of Hormone-Refractory Prostate Cancer

Top of Page