%0 Journal Article %A Katherine R Singleton %A Jihye Kim %A Trista K Hinz %A Lindsay A Marek %A Matias Casas-Selves %A Clark Hatheway %A Aik Choon Tan %A James DeGregori %A Lynn E Heasley %T A Receptor Tyrosine Kinase Network Comprised of FGFRs, EGFR, ERBB2 and MET Drives Growth and Survival of Head and Neck Squamous Carcinoma Cell Lines %D 2013 %R 10.1124/mol.112.084111 %J Molecular Pharmacology %P mol.112.084111 %X Abstract: Our lab has 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, AZ8010, 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. Underrepresented shRNAs in treated cells are expected to target genes important for survival with AZ8010 treatment. Synthetic lethal hits were validated with specific inhibitors and independent shRNAs. We found that multiple alternate receptors provided protection from FGFR inhibition, including 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 triple combination of FGFR, MET and ERBB family inhibitors showed the largest inhibition of growth and induction of apoptosis 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. %U https://molpharm.aspetjournals.org/content/molpharm/early/2013/01/31/mol.112.084111.full.pdf