Cancer cell, 2015-04, Vol.27 (4), p.533-546
- Elkabets, Moshe
- Pazarentzos, Evangelos
- Juric, Dejan
- Sheng, Qing
- Pelossof, Raphael A.
- Brook, Samuel
- Benzaken, Ana Oaknin
- Rodon, Jordi
- Morse, Natasha
- Yan, Jenny Jiacheng
- Liu, Manway
- Das, Rita
- Chen, Yan
- Tam, Angela
- Wang, Huiqin
- Liang, Jinsheng
- Gurski, Joseph M.
- Kerr, Darcy A.
- Rosell, Rafael
- Teixidó, Cristina
- Huang, Alan
- Ghossein, Ronald A.
- Rosen, Neal
- Bivona, Trever G.
- Scaltriti, Maurizio
- Baselga, José
2015
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Elkabets, Moshe
- Pazarentzos, Evangelos
- Juric, Dejan
- Sheng, Qing
- Pelossof, Raphael A.
- Brook, Samuel
- Benzaken, Ana Oaknin
- Rodon, Jordi
- Morse, Natasha
- Yan, Jenny Jiacheng
- Liu, Manway
- Das, Rita
- Chen, Yan
- Tam, Angela
- Wang, Huiqin
- Liang, Jinsheng
- Gurski, Joseph M.
- Kerr, Darcy A.
- Rosell, Rafael
- Teixidó, Cristina
- Huang, Alan
- Ghossein, Ronald A.
- Rosen, Neal
- Bivona, Trever G.
- Scaltriti, Maurizio
- Baselga, José
- Titel
- AXL Mediates Resistance to PI3Kα Inhibition by Activating the EGFR/PKC/mTOR Axis in Head and Neck and Esophageal Squamous Cell Carcinomas
- Ist Teil von
- Cancer cell, 2015-04, Vol.27 (4), p.533-546
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2015
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Upregulation of AXL counteracts PI3Kα inhibition•AXL dimerizes with EGFR and activates the PLCγ-PKC pathway•The EGFR-PLCγ-PKC signaling results in PI3K/AKT-independent activation of mTOR•Inhibition of EGFR, PKC, or AXL reverts resistance to PI3Kα inhibitors Elkabets et al. find that head and neck and esophageal squamous cell carcinomas refractory to PI3Kα inhibition overexpress AXL. They show that AXL interacts with EGFR to activate PLCγ and PKC, leading to PI3K-independent mTOR activation. Inhibition of EGFR, AXL, or PKC reverts resistance to PI3Kα inhibition.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccell.2015.03.010Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4398915
- Format
- –
- Schlagworte
- Animals, Antibodies, Monoclonal, Humanized - pharmacology, Carcinoma, Squamous Cell - metabolism, Cell Line, Tumor, Cetuximab, Class I Phosphatidylinositol 3-Kinases, Drug Resistance, Neoplasm, Esophageal Neoplasms - metabolism, Esophageal Squamous Cell Carcinoma, Head and Neck Neoplasms - metabolism, Humans, Mice, Phosphatidylinositol 3-Kinases - antagonists & inhibitors, Phosphatidylinositol 3-Kinases - genetics, Phosphatidylinositol 3-Kinases - metabolism, Protein Kinase C - metabolism, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins - genetics, Proto-Oncogene Proteins - metabolism, Proto-Oncogene Proteins - physiology, Receptor Protein-Tyrosine Kinases - genetics, Receptor Protein-Tyrosine Kinases - metabolism, Receptor Protein-Tyrosine Kinases - physiology, Signal Transduction, Thiazoles - pharmacology, TOR Serine-Threonine Kinases - metabolism, Xenograft Model Antitumor Assays