Alternative Resistnace Mechanism To Cetuximab In Head And Neck Cancer: From Case Study To Mechanism

Introduction
Innate and acquired resistance to cetuximab, an epithelial growth factor receptor (EGFR) blocker, is a major problem in treating metastatic head and neck squamous cell carcinoma (HNSCC). Although cetuximab significantly prolongs the median overall survival in HNSCC patients, only 15% of the patients experience a partial response, which lasts only several months.

Upregulation of the HER2 and HER3 receptors is a well described resistance mechanism to cetuximab treatment. Here we describe an alternative, mutually exclusive, resistance mechanism though activation of the MET receptor.

Material and method
Genomic, transcriptomics, and proteomics profiling was done on cetuximab-sensitive (Cetux^Sen) and resistant tumor (Cetux^Res) lesions obtained from a patient who had an exceptionally good response to cetuximab monotherapy. Immunohistochemistry (IHC), FISH, and qPCR were applied to confirm MET localization, copy number, and expression, respectively. Both in-vitro and in-vivo studies were used to uncover the molecular mechanism of resistance.

Results and discussion
MET amplification and overexpression were observed in the Cetux^Res tumor compared to the Cetux^Sen tumor. Activation of MET in HNC cell lines was sufficient to confer resistance to cetuximab in-vitro and in-vivo. MET pathway activation reactivated the MAPK pathway, and prevented cetuximab induced- HER2 and HER3 up-regulation.

Conclusions
We show that MET activation is a clinically relevant resistance mechanism to cetuximab in HNSCC. Our data suggests that monitoring MET and HER2/3 expression levels following cetuximab treatment may assist in tailoring combination treatments with cetuximab.