Abstract B268: Tyrosine kinase profiling in head and neck cancer tumors in combination with clinical prognosis factors guides therapeutic combination strategies

Abstract

Abstract Background: Tyrosine kinases (TK) are a particular subgroup of proteins implicated in the genesis/progression of Squamous cell carcinoma of the head and neck (SCCHN). Therapeutic inhibition of several of them has shown to be clinically useful, as is the case of EGFR inhibition with the antibody cetuximab. Identification of the TKs activated in SCCHN is a must in order to adequately target these kinases with available inhibitors. Methods: Here we have investigated activated tyrosine kinases in head and neck cancer tumors derived from patients using a human phospho protein array for 42 receptor tyrosine kinases (RTK). Clinicopathological parameters were reviewed from patient charts to associate activated kinases with prognosis. In vivo xenografted models were used to study the antiproliferative effect of the combination of specific TK inhibitors against them. Results: TK receptors of the EGF and the VEGF family were the mostly activated in tumors derived from patients. EGFR/HER family receptors, such as HER3, were also activated (phosphorylated). These data were corroborated in SCCHN cell lines. In these cells, Akt and FAK kinases, other RTK signalling intermediates, were also activated. Combination of the anti-EGFR-HER2 TK inhibitor lapatinib with dasatinib (that targets FAK) was synergistic in vitro. Combination of lapatinib with the anti-VEGFR TK inhibitor pazopanib resulted in a better trend in response in the in vivo xenografted models. Conclusions: Rational target drug combinations should be based on the identification of activated TK receptors or downstream signalling molecules in association with prognosis. Combination strategies using anti-EGFR/HER, anti-FAK, and anti-VEGFR compounds increases the action of individual treatments and should be considered when design rational clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B268.