Figure 1.

Graphical abstract depicting the mechanisms of inherent and acquired resistance to PI3K inhibition at different vertical nodes along the PI3K/Akt/mTOR pathway. Activating mutations and copy number amplifications in PIK3CA result in marked upregulation of PI3Kα signaling. Acquired resistance develops via activation of the CDK 4/6–cyclin D1 complex that may be blocked simultaneously to overcome this resistance. Alternatively, mTOR inhibition may synergize downstream with PI3Kα inhibition. Conversely, PIK3CA wild-type tumors are independent of PI3Kα activity, which makes them inherently resistant to PI3Kα inhibition. Hence, combining additional inhibition along the pathway may overcome this resistance and improve the efficacy of PI3K inhibitors.