PMID- 23903756
OWN - NLM
STAT- MEDLINE
DCOM- 20140508
LR  - 20220408
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 5
IP  - 196
DP  - 2013 Jul 31
TI  - mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in 
      PIK3CA-mutant breast cancer.
PG  - 196ra99
LID - 10.1126/scitranslmed.3005747 [doi]
AB  - Activating mutations of the PIK3CA gene occur frequently in breast cancer, and 
      inhibitors that are specific for phosphatidylinositol 3-kinase (PI3K) p110alpha, such 
      as BYL719, are being investigated in clinical trials. In a search for correlates 
      of sensitivity to p110alpha 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 
      p110alpha 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 p110alpha-targeted drugs and delay the appearance of resistance.
FAU - Elkabets, Moshe
AU  - Elkabets M
AD  - Human Oncology & Pathogenesis Program and Memorial Sloan Kettering Cancer Center, 
      1275 York Avenue, Box 20, New York, NY 10065, USA.
FAU - Vora, Sadhna
AU  - Vora S
FAU - Juric, Dejan
AU  - Juric D
FAU - Morse, Natasha
AU  - Morse N
FAU - Mino-Kenudson, Mari
AU  - Mino-Kenudson M
FAU - Muranen, Taru
AU  - Muranen T
FAU - Tao, Jessica
AU  - Tao J
FAU - Campos, Ana Bosch
AU  - Campos AB
FAU - Rodon, Jordi
AU  - Rodon J
FAU - Ibrahim, Yasir H
AU  - Ibrahim YH
FAU - Serra, Violeta
AU  - Serra V
FAU - Rodrik-Outmezguine, Vanessa
AU  - Rodrik-Outmezguine V
FAU - Hazra, Saswati
AU  - Hazra S
FAU - Singh, Sharat
AU  - Singh S
FAU - Kim, Phillip
AU  - Kim P
FAU - Quadt, Cornelia
AU  - Quadt C
FAU - Liu, Manway
AU  - Liu M
FAU - Huang, Alan
AU  - Huang A
FAU - Rosen, Neal
AU  - Rosen N
FAU - Engelman, Jeffrey A
AU  - Engelman JA
FAU - Scaltriti, Maurizio
AU  - Scaltriti M
FAU - Baselga, Jose
AU  - Baselga J
LA  - eng
GR  - K99 CA180221/CA/NCI NIH HHS/United States
GR  - R01 CA137008/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Neuregulin-1)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Ribosomal Protein S6)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - Cancer Cell. 2013 Sep 9;24(3):284-6. PMID: 24029226
EIN - Sci Transl Med. 2018 Nov 14;10(467):. PMID: 30429358
MH  - Adult
MH  - Animals
MH  - Breast Neoplasms/drug therapy/*enzymology/*genetics/pathology
MH  - Cell Line, Tumor
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Everolimus
MH  - Female
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Insulin-Like Growth Factor I/pharmacology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Middle Aged
MH  - Multiprotein Complexes/*antagonists & inhibitors/metabolism
MH  - Mutation/*genetics
MH  - Neuregulin-1/pharmacology
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/*pharmacology/*therapeutic use
MH  - Ribosomal Protein S6/metabolism
MH  - Sirolimus/analogs & derivatives/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Treatment Outcome
PMC - PMC3935768
MID - NIHMS551259
COIS- Competing interests: J.B., J.A.E., and N.R. have consulted for Novartis 
      Pharmaceuticals. J.A.E. has also consulted for Sanofi-Aventis, GlaxoSmithKline, 
      Genentech, Abbott, Intellikine, Cell Signaling Technology, Pathway Therapeutics, 
      and Chugai. J.A.E. receives research support from Novartis Pharmaceuticals. A.H. 
      and M.L. are full-time employees of Novartis Pharmaceuticals. C.Q. holds equity 
      in Novartis Pharmaceuticals. J.R. served on an advisory board for Novartis 
      Pharmaceuticals. N.R. serves on advisory boards for AstraZeneca and Millennium. 
      Novartis has filed a patent application for the combination of BYL719 and RAD001.
EDAT- 2013/08/02 06:00
MHDA- 2014/05/09 06:00
PMCR- 2014/02/26
CRDT- 2013/08/02 06:00
PHST- 2013/08/02 06:00 [entrez]
PHST- 2013/08/02 06:00 [pubmed]
PHST- 2014/05/09 06:00 [medline]
PHST- 2014/02/26 00:00 [pmc-release]
AID - 5/196/196ra99 [pii]
AID - 10.1126/scitranslmed.3005747 [doi]
PST - ppublish
SO  - Sci Transl Med. 2013 Jul 31;5(196):196ra99. doi: 10.1126/scitranslmed.3005747.