PIK3CA and cancer: First, the inhibition of mTOR1 induces negative feedback regulation and activation of PI3K-AKT signaling causing survival of cancer cells.71 Second, proteins downstream of mTOR such as 4EBP1, a translation repressor protein can be reactivated to drive the proliferation of cancer cells under long-term rapamycin treatment.72,73 In addition, rapamycin has limited influence on the activation of mTORC2, which plays an active role in tumorigenesis as an important part of the PI3K–mTORC2–AKT axis.60,74 However, some combinatorial strategies of mTOR inhibitors in the clinic have proved beneficial.