Cooperative activation of PDK1 and AKT by MAPK4 enhances cancer growth and resistance to therapy

Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase of the protein A, G, and C (AGC) family kinases that play important roles in regulating cancer cell proliferation, survival, and metabolism. Besides phosphorylating/activating AKT at the cell membrane in a PI3K-dependent manner, PDK1 also exhibits constitutive activity on many other AGC kinases for tumor-promoting activity. In the latter case, PDK1 protein levels dominate its activity. We previously reported that MAPK4, an atypical MAPK, can PI3K-independently promote AKT activation and tumor growth. Here, using triple-negative breast cancer (TNBC) cell models, we demonstrate that MAPK4 can also enhance PDK1 protein synthesis, thus phosphorylate/activate PDK1 substrates beyond AKT. This new MAPK4-PDK1 axis alone lacks vigorous tumor-promoting activity but cooperates with our previously reported MAPK4-AKT axis to promote tumor growth. Besides enhancing resistance to PI3K blockade, MAPK4 also promotes cancer cell resistance to the more stringent PI3K and PDK1 co-blockade, a recently proposed therapeutic strategy. Currently, there is no MAPK4 inhibitor to treat MAPK4-high cancers. Based on the concerted action of MAPK4-AKT and MAPK4-PDK1 axis in promoting cancer, we predict and confirm that co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, suggesting a potential therapeutic strategy to treat MAPK4-high cancers.

Automated summary

Phosphoinositide-dependent kinase-1 (PDK1) is a master kinase that regulates cancer cell proliferation, survival, and metabolism. It phosphorylates/activates AKT and other AGC kinases, including MAPK4, promoting tumor growth. MAPK4 can independently promote AKT activation and tumor growth, and also enhance PDK1 protein synthesis, leading to the activation of PDK1 substrates beyond AKT. Co-targeting AKT and PDK1 effectively represses MAPK4-induced cancer cell growth, providing a potential therapeutic strategy for MAPK4-high cancers.