mTORC1 Inhibition Is Required for Sensitivity to PI3K p110alpha Inhibitors in PIK3GA-Mutant Breast Cancer

摘要

Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (P13K) p110alpha, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110alpha inhibition among PIK3G4-mutant breast cancer cell lines, we observed that sensitivity to BYL719 (as assessed by cell proliferation) was associated with full inhibition of signaling through the TORC1 pathway. Conversely, cancer cells that were resistant to BYL719 had persistently active mTORCI signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORCI signaling) was associated with tumor response to BYL719, and mTORCI was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3G4-mutant cancer cell lines with persistent mTORCI signaling despite PI3K p110alpha blockade (that is, resistance), the addition of the allosteric mTORCI inhibitor RAD001 to the cells along with BYL719 resulted in reversal of resistance in vitro and in vivo. Finally, we found that growth factors such as insulin-like growth factor 1 and neuregulin 1 can activate mammalian target of rapamycin (mTOR) and mediate resistance to BYL719. Our findings suggest that simultaneous administration of mTORCI inhibitors may enhance the clinical activity of p110alpha-targeted drugs and delay the appearance of resistance.