PMID- 25873175
OWN - NLM
STAT- MEDLINE
DCOM- 20150623
LR  - 20221207
IS  - 1878-3686 (Electronic)
IS  - 1535-6108 (Print)
IS  - 1535-6108 (Linking)
VI  - 27
IP  - 4
DP  - 2015 Apr 13
TI  - AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis 
      in head and neck and esophageal squamous cell carcinomas.
PG  - 533-46
LID - S1535-6108(15)00098-7 [pii]
LID - 10.1016/j.ccell.2015.03.010 [doi]
AB  - Phosphoinositide-3-kinase (PI3K)-alpha inhibitors have shown clinical activity in 
      squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations 
      or amplification. Studying models of therapeutic resistance, we have observed 
      that SCC cells that become refractory to PI3Kalpha inhibition maintain 
      PI3K-independent activation of the mammalian target of rapamycin (mTOR). This 
      persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL 
      is overexpressed in resistant tumors from both laboratory models and patients 
      treated with the PI3Kalpha inhibitor BYL719. AXL dimerizes with and phosphorylates 
      epidermal growth factor receptor (EGFR), resulting in activation of phospholipase 
      Cgamma (PLCgamma)-protein kinase C (PKC), which, in turn, activates mTOR. Combined 
      treatment with PI3Kalpha and either EGFR, AXL, or PKC inhibitors reverts this 
      resistance.
CI  - Copyright (c) 2015 Elsevier Inc. All rights reserved.
FAU - Elkabets, Moshe
AU  - Elkabets M
AD  - Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer 
      Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
FAU - Pazarentzos, Evangelos
AU  - Pazarentzos E
AD  - Division of Hematology and Oncology, Department of Medicine, Helen Diller 
      Comprehensive Cancer Center, University of California, San Francisco, 600 16th 
      Street, San Francisco, CA 94158, USA.
FAU - Juric, Dejan
AU  - Juric D
AD  - Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, 
      USA.
FAU - Sheng, Qing
AU  - Sheng Q
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Pelossof, Raphael A
AU  - Pelossof RA
AD  - Computation Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York 
      Avenue, Box 20, New York, NY 10065, USA.
FAU - Brook, Samuel
AU  - Brook S
AD  - Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer 
      Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
FAU - Benzaken, Ana Oaknin
AU  - Benzaken AO
AD  - Medical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, 
      Barcelona 08035, Spain.
FAU - Rodon, Jordi
AU  - Rodon J
AD  - Medical Oncology, Vall d'Hebron Institute of Oncology, Pg Vall d'Hebron, 119-129, 
      Barcelona 08035, Spain.
FAU - Morse, Natasha
AU  - Morse N
AD  - Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer 
      Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
FAU - Yan, Jenny Jiacheng
AU  - Yan JJ
AD  - Division of Hematology and Oncology, Department of Medicine, Helen Diller 
      Comprehensive Cancer Center, University of California, San Francisco, 600 16th 
      Street, San Francisco, CA 94158, USA.
FAU - Liu, Manway
AU  - Liu M
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Das, Rita
AU  - Das R
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Chen, Yan
AU  - Chen Y
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Tam, Angela
AU  - Tam A
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Wang, Huiqin
AU  - Wang H
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Liang, Jinsheng
AU  - Liang J
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Gurski, Joseph M
AU  - Gurski JM
AD  - Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, 
      USA.
FAU - Kerr, Darcy A
AU  - Kerr DA
AD  - Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, 
      USA.
FAU - Rosell, Rafael
AU  - Rosell R
AD  - Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet s/n, 
      08916 Badalona, Spain; Pangaea Biotech SL, Laboratorio de Oncologia, Hospital 
      Universitario Quiron Dexeus, C/ Sabino Arana 5-19, 08028 Barcelona, Spain.
FAU - Teixido, Cristina
AU  - Teixido C
AD  - Pangaea Biotech SL, Laboratorio de Oncologia, Hospital Universitario Quiron 
      Dexeus, C/ Sabino Arana 5-19, 08028 Barcelona, Spain.
FAU - Huang, Alan
AU  - Huang A
AD  - Oncology Translational Medicine, Novartis Institutes for BioMedical Research, 100 
      Technology Square, Cambridge, MA 02139, USA.
FAU - Ghossein, Ronald A
AU  - Ghossein RA
AD  - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 
      10065, USA.
FAU - Rosen, Neal
AU  - Rosen N
AD  - Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer 
      Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Molecular Pharmacology 
      Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
FAU - Bivona, Trever G
AU  - Bivona TG
AD  - Division of Hematology and Oncology, Department of Medicine, Helen Diller 
      Comprehensive Cancer Center, University of California, San Francisco, 600 16th 
      Street, San Francisco, CA 94158, USA.
FAU - Scaltriti, Maurizio
AU  - Scaltriti M
AD  - Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer 
      Center, 1275 York Avenue, Box 20, New York, NY 10065, USA. Electronic address: 
      scaltrim@mskcc.org.
FAU - Baselga, Jose
AU  - Baselga J
AD  - Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer 
      Center, 1275 York Avenue, Box 20, New York, NY 10065, USA; Department of 
      Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New 
      York, NY 10065, USA. Electronic address: baselgaj@mskcc.org.
LA  - eng
SI  - GEO/GSE61515
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - DP2 CA174497/CA/NCI NIH HHS/United States
GR  - K12 CA087723/CA/NCI NIH HHS/United States
GR  - R01 CA169338/CA/NCI NIH HHS/United States
GR  - T32 CA071345/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Cancer Cell
JT  - Cancer cell
JID - 101130617
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Thiazoles)
RN  - 08W5N2C97Q (Alpelisib)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - PQX0D8J21J (Cetuximab)
RN  - 0 (Axl Receptor Tyrosine Kinase)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/pharmacology
MH  - Carcinoma, Squamous Cell/*metabolism
MH  - Cell Line, Tumor
MH  - Cetuximab
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Drug Resistance, Neoplasm
MH  - Esophageal Neoplasms/*metabolism
MH  - Esophageal Squamous Cell Carcinoma
MH  - Head and Neck Neoplasms/*metabolism
MH  - Humans
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase C/metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins/genetics/metabolism/*physiology
MH  - Receptor Protein-Tyrosine Kinases/genetics/metabolism/*physiology
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Thiazoles/pharmacology
MH  - Xenograft Model Antitumor Assays
MH  - Axl Receptor Tyrosine Kinase
PMC - PMC4398915
MID - NIHMS677397
COIS- Conflict of interest J.B., D.J. and N.R. have consulted for Novartis 
      Pharmaceuticals. A.H., Q.S., J.J.Y., R.D., Y.C., A.T., H.W., J.L., and M.L. are 
      full-time employees of Novartis Pharmaceuticals.
EDAT- 2015/04/16 06:00
MHDA- 2015/06/24 06:00
PMCR- 2016/04/13
CRDT- 2015/04/16 06:00
PHST- 2014/08/31 00:00 [received]
PHST- 2015/01/11 00:00 [revised]
PHST- 2015/03/16 00:00 [accepted]
PHST- 2015/04/16 06:00 [entrez]
PHST- 2015/04/16 06:00 [pubmed]
PHST- 2015/06/24 06:00 [medline]
PHST- 2016/04/13 00:00 [pmc-release]
AID - S1535-6108(15)00098-7 [pii]
AID - 10.1016/j.ccell.2015.03.010 [doi]
PST - ppublish
SO  - Cancer Cell. 2015 Apr 13;27(4):533-46. doi: 10.1016/j.ccell.2015.03.010.