Inhibiting MAPK4 Reduced Prostate Cancer Growth

Research led by a team at Baylor College of Medicine reveals that the enzyme MAPK4 activates androgen receptor (AR) and AKT, molecules at the core of two cellular signaling pathways known to promote prostate cancer growth and resistance to standard therapy. The study was published in the Journal of Clinical Investigation. 

The team found that  inhibiting MAPK4 simultaneously inactivated both AR and AKT and stopped cancer growth in animal models. "Scientists already knew that both the AR and the AKT pathways can drive prostate cancer," said corresponding author Feng Yang. "One complication with targeting AR (for instance, with medical castration therapy, including the most advanced agents such as enzalutamide, apalutamide and abiraterone) or AKT is that there is a reciprocal crosstalk between these pathways. When AR is inhibited, AKT gets activated, and vice-versa, therefore tackling these pathways to control cancer growth is complex."

In the current study, the researchers found that MAPK4 also activates the AR signaling pathway by enhancing the production and stabilization of GATA2, a factor that is crucial for the synthesis and activation of AR. Further experiments showed that MAPK4 triggered the concerted activation of both AR and AKT pathways by independent mechanisms, and this promoted prostate cancer growth and resistance to castration therapy, a standard medical treatment for advanced/metastatic prostate cancer. Importantly, genetically knocking down MAPK4 reduced the activation of both AR and AKT pathways and inhibited the growth, including castration-resistant growth, of prostate cancer in animal models. The researchers anticipate that knocking down MAPK4 also could reduce the growth of other cancer types in which MAPK4 is involved.

"Our findings suggest the possibility that regulating MAPK4 activity could result in a novel therapeutic approach for prostate cancer," Yang said. "We are interested in finding an inhibitor of MAPK4 activity that could help better treat prostate cancer and other cancer types in the future."