Insulin growth factor 1 like receptor (IGF-1R)

BMC Cancer

Research Article

Shay Bourgeois¹  Shyhmin Huang¹  Gopal Iyer¹  Paul M. Harari¹  James Price¹  Eric Armstrong¹ 

[1] Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, 53792, Madison, USA;

关键词: Head and neck cancer;    Clinical antibody cetuximab;    Heterodimerization;    Phosphorylation;    Picropodophyllin;   

DOI  :  10.1186/s12885-016-2796-x

 received in 2016-02-24, accepted in 2016-09-08,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood.MethodsIn this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab. Co-immunoprecipitation, small molecule inhibitors against phospho-Src and IGF-1R, quantitative western blot of EGFR and Src phosphorylation, cell proliferation assays were used to suggest the role of IGF-1R mediated phosphorylation of specific tyrosine Y845 on EGFR via increased heterodimerization of EGFR and IGF-1R in cetuximab resistant cells.ResultsHeterodimerization of EGFR with IGF-1R was increased in cetuximab resistant HNSCC cell line UMSCC6. Basal levels of phosphorylated EGFR Y845 showed significant increase in the presence of cetuximab. Surprisingly, this activated Y845 level was not inhibited in the presence of Src inhibitor PP1. Instead, inhibition of IGF-1R by picropodophyllin (PPP) reduced the EGFR Y845 levels. Taken together, these results suggest that heterodimerization of EGFR with IGF-1R can lead to increased activity of EGFR and may be an important platform for cetuximab mediated signaling in head and neck tumors that have become resistant to anti-EGFR therapy.ConclusionsEGFR-IGF-1R interaction has a functional consequence of phosphorylation of EGFR Y845 in cetuximab resistant HNSCC cells and dual targeting of EGFR and IGF-1R is a promising therapeutic strategy.

【 授权许可】

CC BY   
© The Author(s). 2016