RRC ID 44560
Author Elkabets M, Vora S, Juric D, Morse N, Mino-Kenudson M, Muranen T, Tao J, Campos AB, Rodon J, Ibrahim YH, Serra V, Rodrik-Outmezguine V, Hazra S, Singh S, Kim P, Quadt C, Liu M, Huang A, Rosen N, Engelman JA, Scaltriti M, Baselga J.
Title mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
Journal Sci Transl Med
Abstract Activating mutations of the PIK3CA gene occur frequently in breast cancer, and inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110α, such as BYL719, are being investigated in clinical trials. In a search for correlates of sensitivity to p110α inhibition among PIK3CA-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 mTORC1 signaling, although Akt phosphorylation was inhibited. Similarly, in patients, pS6 (residues 240/4) expression (a marker of mTORC1 signaling) was associated with tumor response to BYL719, and mTORC1 was found to be reactivated in tumors from patients whose disease progressed after treatment. In PIK3CA-mutant cancer cell lines with persistent mTORC1 signaling despite PI3K p110α blockade (that is, resistance), the addition of the allosteric mTORC1 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 mTORC1 inhibitors may enhance the clinical activity of p110α-targeted drugs and delay the appearance of resistance.
Volume 5(196)
Pages 196ra99
Published 2013-7-31
DOI 10.1126/scitranslmed.3005747
PII 5/196/196ra99
PMID 23903756
PMC PMC3935768
MeSH Adult Animals Breast Neoplasms / drug therapy Breast Neoplasms / enzymology* Breast Neoplasms / genetics* Breast Neoplasms / pathology Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases Drug Resistance, Neoplasm / drug effects Everolimus Female Humans Inhibitory Concentration 50 Insulin-Like Growth Factor I / pharmacology Mechanistic Target of Rapamycin Complex 1 Mice Middle Aged Multiprotein Complexes / antagonists & inhibitors* Multiprotein Complexes / metabolism Mutation / genetics* Neuregulin-1 / pharmacology Phosphatidylinositol 3-Kinases / antagonists & inhibitors* Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use* Ribosomal Protein S6 / metabolism Sirolimus / analogs & derivatives Sirolimus / pharmacology Sirolimus / therapeutic use TOR Serine-Threonine Kinases / antagonists & inhibitors* TOR Serine-Threonine Kinases / metabolism Treatment Outcome
IF 17.2
Times Cited 61
Human and Animal Cells