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: Moshe Elkabets, Sadhna Vora, Dejan Juric, Natasha Morse, Mari Mino-Kenudson, Taru Muranen, Jessica Tao, Ana Bosch Campos, Jordi Rodon, Yasir H Ibrahim, Violeta Serra, Vanessa Rodrik-Outmezguine, Saswati Hazra, Sharat Singh, Phillip Kim, Cornelia Quadt, Manway Liu, Alan Huang, Neal Rosen, Jeffrey A Engelman, Maurizio Scaltriti, José Baselga
• Journal: Science translational medicine (Sci Transl Med) Vol. 5 Issue 196 Pg. 196ra99 (Jul 31 2013) ISSN: 1946-6242 [Electronic] United States
• PMID: 23903756 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Multiprotein Complexes
• Neuregulin-1
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Ribosomal Protein S6
• Insulin-Like Growth Factor I
• Everolimus
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adult
• Animals
• Breast Neoplasms (drug therapy, enzymology, genetics, 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, metabolism)
• Mutation (genetics)
• Neuregulin-1 (pharmacology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Ribosomal Protein S6 (metabolism)
• Sirolimus (analogs & derivatives, pharmacology, therapeutic use)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Treatment Outcome