Abstract B35: Alternate receptor tyrosine kinases provide protection from FGFR inhibition in HNSCC cells as identified by genome-wide shRNA screening

Abstract

Abstract The efficacy of many biologically targeted cancer therapies is limited by intrinsic and acquired resistance. Head and neck squamous carcinoma (HNSCC) patients show only a 4–10% response to the epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, despite EGFR over-expression in over 90% of tumors. Our lab has previously shown that gefitinib insensitive non-small cell lung cancer (NSCLC) cell lines exhibit dominant autocrine fibroblast growth factor receptor (FGFR) signaling. RNAi-based loss-of-function screens are an important tool to identify synthetic lethal interactions between the inhibition of two genes in order to efficiently identify functional survival mechanisms and potent drug combinations. We deployed a whole genome screen to identify genes whose knockdown potentiated the inhibitory effect of the FGFR inhibitor, AZ12908010, in HNSCC cell lines. We found that multiple alternate receptors provided protection from FGFR inhibition in these cell lines, including the receptor tyrosine kinases (RTKs) epidermal growth factor receptor 2 (ErbB2) and hepatocyte growth factor receptor (Met). We validated the results of the screen by showing that specific knockdown of either ErbB2 or Met in combination with FGFR inhibitor treatment 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 ErbB2 or Met. The combination therapies did not lead to greater inhibition of growth in the cell lines where ErbB2 and Met were not identified as synthetic lethal with FGFR. We extended the study to find that the combination of knockdown of either ErbB2 or Met with FGFR inhibition decreased the growth of additional cell lines, indicating that the combination therapies could be broadly applicable. 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 and either ErbB family members or Met.