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mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer

Elkabets, Moshe; Vora, Sadhna; Juric, Dejan; Morse, Natasha; Mino-Kenudson, Mari; Muranen, Taru; Tao, Jessica; Campos, Ana Bosch LU ; Rodon, Jordi and Ibrahim, Yasir H, et al. (2013) In Science Translational Medicine 5(196). p.1-14
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... (More)

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.

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keywords
Adult, Animals, Breast Neoplasms, Cell Line, Tumor, Drug Resistance, Neoplasm, Everolimus, Female, Humans, Inhibitory Concentration 50, Insulin-Like Growth Factor I, Mice, Middle Aged, Multiprotein Complexes, Mutation, Neuregulin-1, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Ribosomal Protein S6, Sirolimus, TOR Serine-Threonine Kinases, Treatment Outcome, Journal Article, Research Support, Non-U.S. Gov't
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Science Translational Medicine
volume
5
issue
196
pages
1 - 14
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:84883624766
ISSN
1946-6242
DOI
10.1126/scitranslmed.3005747
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English
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c8bdf825-d4dd-4f89-b10b-db99e00a1ca6
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2016-12-02 16:19:30
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2018-03-18 05:06:52
@article{c8bdf825-d4dd-4f89-b10b-db99e00a1ca6,
  abstract     = {<p>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.</p>},
  articleno    = {196ra99},
  author       = {Elkabets, Moshe and Vora, Sadhna and Juric, Dejan and Morse, Natasha and Mino-Kenudson, Mari and Muranen, Taru and Tao, Jessica and Campos, Ana Bosch and Rodon, Jordi and Ibrahim, Yasir H and Serra, Violeta and Rodrik-Outmezguine, Vanessa and Hazra, Saswati and Singh, Sharat and Kim, Phillip and Quadt, Cornelia and Liu, Manway and Huang, Alan and Rosen, Neal and Engelman, Jeffrey A and Scaltriti, Maurizio and Baselga, José},
  issn         = {1946-6242},
  keyword      = {Adult,Animals,Breast Neoplasms,Cell Line, Tumor,Drug Resistance, Neoplasm,Everolimus,Female,Humans,Inhibitory Concentration 50,Insulin-Like Growth Factor I,Mice,Middle Aged,Multiprotein Complexes,Mutation,Neuregulin-1,Phosphatidylinositol 3-Kinases,Protein Kinase Inhibitors,Ribosomal Protein S6,Sirolimus,TOR Serine-Threonine Kinases,Treatment Outcome,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {07},
  number       = {196},
  pages        = {1--14},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {mTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer},
  url          = {http://dx.doi.org/10.1126/scitranslmed.3005747},
  volume       = {5},
  year         = {2013},
}