Fig. 6.

Model of response to PI3K inhibition in anti-estrogen-resistant, PTEN-deficient, ER+ breast tumors. Left: PI3K signaling engages AKT, which drives mTORC1-induced translation of mRNAs encoding Cyclin D1/D3. Cyclin D1/D3 bind CDK4/CDK6 to promote Rb phosphorylation, which derepresses E2F transcription factors to drive expression of genes that promote proliferation and suppress apoptosis. CDK6 phosphorylates FoxM1 to promote FoxM1 stability, which suppresses senescence. Middle: Short-term PI3K inhibition with BYL719/GSK2636771 decreases AKT/mTORC1 signaling and Cyclin D1/D3 levels, decreasing CDK4/6 activity, P-Rb, and FoxM1 stability. Unphosphorylated Rb binds E2F proteins to suppress expression of pro-growth and anti-apoptosis genes. Right: After long-term PI3K inhibition, AKT activation is partially restored but mTORC1 remains inhibited, suggesting that AKT signaling becomes disconnected from mTORC1. Despite continued suppression of Cyclin D1/D3, CDK4/6 activity is partially restored as indicated by partial recovery of P-Rb and FoxM1.