Synthetic lethality by co-targeting mitochondrial apoptosis and PI3K/Akt/mTOR signaling

Small-molecule inhibitors that antagonize anti-apoptotic Bcl-2 proteins such as BH3 mimetics are currently considered as promising cancer therapeutics to engage the mitochondrial pathway of apoptosis in cancer cells. However, BH3 mimetics may be effective as monotherapy only in cancers that critically depend on anti-apoptotic Bcl-2 proteins for their survival. Since most cancers have evolved multiple strategies to evade programmed cell death, concomitant targeting of several signaling transduction pathways becomes more and more relevant. The current review highlights the potential of combined inhibition of anti-apoptotic Bcl-2 proteins together with the PI3K/Akt/mTOR signaling cascade to trigger apoptosis in cancer cells.