The potentiative cytotoxic effect of IGF1R and EGFR inhibition on the Head and Neck Cancer Proteome

Head and neck cancers are the sixth most common cancer worldwide. Combinatorial targeted therapy has the potential to reduce drug resistance and increase cytotoxicity to head and neck squamous cell carcinoma (HNSCC). Using drug combinations is especially important when targeting the epidermal growth factor receptor (EGFR) since we previously demonstrated that activation of the insulin-like growth factor 1 receptor (IGF1R) is a mechanism for resistance against EGFR inhibition and that a combination of an IGF1R inhibitor, BMS754807, and an EGFR inhibitor, BMS599626, robustly inhibited the growth of HNSCC cell lines in vitro. To examine the mechanism of cytotoxicity, we performed protein pathway activation mapping via reverse phase protein array (RPPA) analysis of 145 proteins and phosphoproteins in five HNSCC cell lines to map key proteins and phosphoproteins important in tumorigenesis. By performing principal component analysis, calculating log fold changes, and constructing protein networks, we were able to provide evidence to support the hypothesis that the combination of IGF1R and EGFR inhibitors has a potentiative effect on inhibiting receptor tyrosine kinase signaling. The effects of the individual drugs are amplified, demonstrating that the combination more robustly inhibits the pathways of both receptors.