title: mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer.
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.
authors.affiliation: Human Oncology & Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Elkabets
authors.forename: Sadhna
authors.initials: S
authors.lastname: Vora
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.forename: Natasha
authors.initials: N
authors.lastname: Morse
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.forename: Jessica
authors.initials: J
authors.lastname: Tao
authors.forename: Ana Bosch
authors.initials: AB
authors.lastname: Campos
authors.forename: Jordi
authors.initials: J
authors.lastname: Rodon
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.forename: Vanessa
authors.initials: V
authors.lastname: Rodrik-Outmezguine
authors.forename: Saswati
authors.initials: S
authors.lastname: Hazra
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.forename: Phillip
authors.initials: P
authors.lastname: Kim
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.forename: Manway
authors.initials: M
authors.lastname: Liu
authors.forename: Alan
authors.initials: A
authors.lastname: Huang
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000068338:Everolimus; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020890:Neuregulin-1 / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D038601:Ribosomal Protein S6 / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D007334:Insulin-Like Growth Factor I; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C484760:PIK3CA protein, human
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