TY - JOUR
T1 - AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR Axis in Head and neck and esophageal squamous cell carcinomas
AU - Elkabets, Moshe
AU - Pazarentzos, Evangelos
AU - Juric, Dejan
AU - Sheng, Qing
AU - Pelossof, Raphael A.
AU - Brook, Samuel
AU - Benzaken, Ana Oaknin
AU - Rodon, Jordi
AU - Morse, Natasha
AU - Yan, Jenny Jiacheng
AU - Liu, Manway
AU - Das, Rita
AU - Chen, Yan
AU - Tam, Angela
AU - Wang, Huiqin
AU - Liang, Jinsheng
AU - Gurski, Joseph M.
AU - Kerr, Darcy A.
AU - Rosell, Rafael
AU - Teixidó, Cristina
AU - Huang, Alan
AU - Ghossein, Ronald A.
AU - Rosen, Neal
AU - Bivona, Trever G.
AU - Scaltriti, Maurizio
AU - Baselga, José
N1 - Funding Information: This work was funded by the Cycle for Survival (to J.B. and M.S.), Banco Bilbao Vizcaya Argentaria (BBVA) Foundation (Tumor Biomarker Research Program) and a Molecular Cytology Core Facility-Core grant (P30 CA0087748). M.E. is an International Sephardic Education Foundation postdoctoral fellow. D.J. is funded by a NIH Training Grant (T32 CA-71345-15). T.G.B. is funded by the NIH Director’s Award DP2 CA174497. Publisher Copyright: © 2015 Elsevier Inc.
PY - 2015/4/13
Y1 - 2015/4/13
N2 - Phosphoinositide-3-kinase (PI3K)-α 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 PI3Kα 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 PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
AB - Phosphoinositide-3-kinase (PI3K)-α 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 PI3Kα 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 PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
UR - http://www.scopus.com/inward/record.url?scp=84928015512&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ccell.2015.03.010
DO - https://doi.org/10.1016/j.ccell.2015.03.010
M3 - Article
C2 - 25873175
SN - 1535-6108
VL - 27
SP - 533
EP - 546
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -
