Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2796-x) contains supplementary material, which is available to authorized users.
Highlights
The epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers
Insulin growth factor (IGF)-1R, a receptor tyrosine kinases (RTKs) known to be involved in malignant transformation and expressed in tumors was upregulated in resistant cells when compared to sensitive cells (Fig. 1b and c)
Quantification of the immunoblots revealed that Insulin growth factor 1 like receptor (IGF-1R) protein level was induced by two- fold within 2 h of exposure to cetuximab in resistant cells (Fig. 1c)
Summary
The 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. The cancer genome atlas (TCGA) has identified amplification and mutation of EGFR in a proportion of human papillomavirus (HPV) positive and negative head and neck cancers [3]. This overexpression of EGFR leads to dysregulated signaling in HNSCC [4]. The onset of EGFR resistance can trigger alternative signaling pathways through association with other receptor tyrosine kinases [14, 15] or Gprotein coupled receptors (GPCRs) [16] to maintain the tumor phenotype but these precise mechanisms remain only partially understood
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
