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| Status |
Public on May 03, 2013 |
| Title |
A receptor tyrosine kinase network comprised of FGFRs, EGFR, ERBB2, and MET drives growth and survival of HNSCC cell lines. |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
We have previously shown that some gefitinib insensitive head and neck squamous cell carcinoma (HNSCC) cell lines exhibit dominant autocrine fibroblast growth factor receptor (FGFR) signaling. Herein, we deployed a whole genome loss-of-function screen to identify genes whose knockdown potentiated the inhibitory effect of the FGFR inhibitor, AZ12908010, in HNSCC cell lines. Three HNSCC cell lines expressing a genome-wide shRNA library were treated with AZ8010 and the abundance of shRNA sequences was assessed by deep sequencing. Synthetic lethal hits were validated through use of specific inhibitors and independent shRNAs. We found that multiple alternate receptors provided protection from FGFR inhibition, including the receptor tyrosine kinases (RTKs), epidermal growth factor receptor 2 (ERBB2) and hepatocyte growth factor receptor (MET). We showed that specific knockdown of either ERBB2 or MET in combination with FGFR inhibition led to increased inhibition of growth relative to FGFR tyrosine kinase inhibitor (TKI) treatment alone. These results were confirmed using specific small molecule inhibitors of either ERBB family members or MET. Moreover, the combination of FGFR, MET and ERBB family inhibitors showed the largest inhibition of growth as compared to the double combinations. These results reveal a role for alternate RTKs in maintaining pro-growth and survival signaling in HNSCC cells in the setting of FGFR inhibition. Thus, improved therapies for HNSCC patients could involve rationally designed combinations of TKIs targeting FGFR, ERBB family members and MET.
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| Overall design |
Using a genome-wide shRNA library in combination with deep sequencing, we screened for gene targets that were synthetic lethal with the FGFR inhibitor, AZ12908010 in HNSCC cells. Three HNSCC cell lines were screened in triplicate and the abundance of shRNA sequences in drug treated cells was compared to control treated cells.
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| Contributor(s) |
Singleton KR, Kim J, Hinz TK, Marek LA, Casas-Selves M, Hatheway C, Tan AC, DeGregori J, Heasley LE |
| Citation(s) |
23371912 |
| Submission date |
Jul 12, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Jihye Kim |
| E-mail(s) |
kim.jihey@gmail.com
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| Phone |
7209755448
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| Organization name |
Cleveland Clinic
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| Department |
Quantitative Health Sciences
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| Street address |
9500 Euclid Ave.
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| City |
Cleveland |
| State/province |
Ohio |
| ZIP/Postal code |
44195 |
| Country |
USA |
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| Platforms (1) |
| GPL10999 |
Illumina Genome Analyzer IIx (Homo sapiens) |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA170525 |
| SRA |
SRP014213 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE39305_Heasley_AZ8010.txt.gz |
2.8 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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