Genomics

Dataset Information

0

A receptor tyrosine kinase network comprised of FGFRs, EGFR, ERBB2, and MET drives growth and survival of HNSCC cell lines.


ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39305 | GEO | 2013/05/03

SECONDARY ACCESSION(S): PRJNA170525

REPOSITORIES: GEO

Similar Datasets

| E-GEOD-39305 | biostudies-arrayexpress
| E-GEOD-43037 | biostudies-arrayexpress
2022-10-13 | PXD007769 | Pride
| E-GEOD-41718 | biostudies-arrayexpress
2013-06-20 | GSE43037 | GEO
2020-05-15 | PXD009433 | Pride
2021-02-04 | PXD013810 | Pride
2022-08-31 | GSE205787 | GEO
2021-11-23 | GSE189461 | GEO
2013-08-07 | GSE41718 | GEO