Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt

SUMMARY

The retinoblastoma (Rb) protein exerts its tumor suppressor function primarily by inhibiting the E2F family of transcription factors that govern cell cycle progression. However, it remains largely elusive whether hyper-phosphorylated, non-E2F1-interacting form, of Rb has any physiological role. Here, we report that hyper-phosphorylated Rb directly binds to, and suppresses the function of mTORC2, but not mTORC1. Mechanistically, Rb, but not p107 nor p130, interacts with Sin1 and blocks the access of Akt to mTORC2, leading to attenuated Akt activation and increased sensitivity to chemotherapeutic drugs. As such, inhibition of Rb phosphorylation by depleting cyclin D, or using CDK4/6 inhibitors, releases Rb-mediated mTORC2 suppression. This, in turn, leads to elevated Akt activation to confer resistance to chemotherapeutic drugs in Rb-proficient cells, which can be attenuated with Akt inhibitors. Therefore, our work provides a molecular basis for the synergistic usage of CDK4/6 and Akt inhibitors in treating Rb-proficient cancer.

Zhang et al report that hyper-phosphorylated Rb also plays a tumor suppressive role partly through binding Sin1 to inhibit mTORC2-mediated activation of Akt. Thus, inhibiting Rb phosphorylation by depletion of cyclin D or CDK4/6 inhibitor leads to elevated Akt-pS473 to confer drug resistance, which can be attenuated by Akt inhibitors.

Abstract