Bcl-xl and Mcl-1 are the major determinants of the apoptotic response to dual PI3K and MEK blockage.

The dual targeting of PI3K-AKT-mTOR and Ras-Raf-MEK-ERK pathways is a potential anticancer therapy, but unfortunately, the response rate has been low in early phase clinical trials. Pre-clinical models have suggested that an apoptotic response to dual PI3K and MEK targeting is relatively rare and understanding apoptotic avoidance could lead to increased clinical efficiency. This study investigated solid cancer cell lines, which are known to be sensitive to dual PI3K and MEK inhibition but to have a limited apoptotic response. The cells were exposed to dual PI3K and MEK blockage in combination with a panel of additional pharmacological agents and cytotoxicity and apoptosis were analyzed. Our results indicated that the BH3 mimetic ABT-263, the HDAC inhibitor entinostat and the multikinase inhibitor dasatinib increased the cytotoxicity and apoptotic response of dual PI3K and MEK targeting. Furthermore, ABT-263 and entinostat was able to induce apoptosis in combination with single agent PI3K and MEK inhibitors. Protein expression, immunoprecipitation and siRNA knockdown models suggested that Bcl-xl and Mcl-1 were the most important factors circumventing PI3K and/or MEK inhibition-mediated apoptosis. The results suggest that the cytotoxicity of PI3K and/or MEK inhibitor treatments can be augmented by combinatory approaches targeting anti-apoptotic mediators Bcl-xl and Mcl-1.