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| Status |
Public on Apr 12, 2015 |
| Title |
AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Phosphoinositide-3-kinase (PI3K)-α inhibitors are clinically active in squamous carcinoma (SCC) of the head and neck (H&N) bearing mutations or amplification of PIK3CA. We aimed to identify potential mechanism of resistance and have observed that SCCs cells overcome the antitumor effects of the PI3Kα inhibitor BYL719 by maintaining PI3K-independent activation of the mammalian target of rapamycin (mTOR). The persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. We found that AXL is overexpressed in resistant tumors, dimerizes with the epidermal growth factor receptor (EGFR), phosphorylates EGFR tyrosine 1173, resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC) that, in turn, activates mTOR. Finally, simultaneous treatment with PI3Kα and either EGFR, AXL or PKC inhibitors reverts this resistance.
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| Overall design |
RNAseq from acquired resistant cells CAL33B, K180B were compared to their parental counterpart CAL33 and K180, respectively. K180 is a shortcut of KYSE180, and B stands for BYL719. Duplicate of parental sensitive cells and K180B, and triplicate for CAL33B.
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| Contributor(s) |
Elkabets M, Pazarentzos E, Sheng Q, Pelossof RA, Brook S, Morse N, Yan JJ, Liu M, Das R, Chen Y, Tam A, Wang H, Liang J, Huang A, Ghissein RA, Rosen N, Bivona TG, Scaltriti M, Baselga J, Juric D, Benzaken AO, Rodon J, Gurski JM, Kerr DA, Rosell R, Teixidó C |
| Citation(s) |
25873175 |
| Submission date |
Sep 17, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
Nicholas D Socci |
| E-mail(s) |
soccin@mskcc.org
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Department |
Computational & Systems Biology Program
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| Lab |
Bioinformatics Core
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| Street address |
1275 York Ave
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10021 |
| Country |
USA |
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| Platforms (1) |
| GPL17303 |
Ion Torrent Proton (Homo sapiens) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA261341 |
| SRA |
SRP047251 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE61515_geneCounts_p4180_SubSet_20140916.txt.gz |
535.4 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Processed data are available on Series record |
| Raw data are available in SRA |
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