eEF2K activity determines synergy to co-treatment of cancer cells with PI3K and MEK inhibitors

Mol Cell Proteomics. 2022 May 2:100240. doi: 10.1016/j.mcpro.2022.100240. Online ahead of print.ABSTRACTPI3K-mTOR and MEK/MAPK are the most frequently dysregulated signaling pathways in cancer. A problem that limits the success of therapies that target individual PI3K-MAPK members is that these pathways converge to regulate downstream functions and often compensate each other, leading to drug resistance and transient responses to therapy. In order to overcome resistance, therapies based on co-treatments with PI3K/AKT and MEK/MAPK inhibitors are now being investigated in clinical trials but the mechanisms of sensitivity to co-treatment are not fully understood. Using LC-MS/MS based phosphoproteomics, we found that eEF2K, a key convergence point downstream of MAPK and PI3K pathways, mediates synergism to co-treatment with trametinib plus pictilisib (which target MEK1/2 and PI3Kα/δ, respectively). Inhibition of eEF2K by siRNA or with a small molecule inhibitor reversed the anti-proliferative effects of the co-treatment with PI3K plus MEK inhibitors in a cell model specific manner. Systematic analysis in 12 acute myeloid leukemia (AML) cell lines revealed that eEF2K activity was increased in cells for which PI3K plus MEKi co-treatment is synergistic, while PKC potentially mediated resistance to such co-treatment. Together, our study uncovers eEF2K activity as a key mediator of responses to PI3Ki plus MEKi and as a potential biomarker to predict synergy to co-treatment in cancer...
Source: Molecular and Cellular Proteomics : MCP - Category: Molecular Biology Authors: Source Type: research