Evaluation of gene expression changes upon acquired resistance to anti-EGFR treatment in head and neck squamous cell carcinoma
We deciphered molecular mechanisms associated with acquired resistance to anti-EGFR targeted therapy in head and neck squamous cell carcinoma (HNSCC) by comparing gene expression profiles in cetuximab-sensitive and -resistant patient-derived xenograft (PDX) models of HNSCC. We generated and validated several HNSCC PDX models. Resistance mechanisms to anti-EGFR therapy were investigated in one of these PDX models (UCLHN04). First, sensitivity to cetuximab treatment was tested. This model showed high sensitivity to this drug. We induced acquired resistance to anti-EGFR therapy in this sensitive model by treating it chronically with anti-EGFR monoclonal antibody (cetuximab, 30 mg/kg/week) until resistance ensues. RNA-seq analysis was performed on samples coming from untreated and cetuximab-resistant PDX, revealing major changes of expression at the mRNA level. Overall design: We induced acquired resistance to anti- EGFR therapy in the a sensitive model by treating it chronically with anti-EGFR monoclonal antibody (cetuximab, 30 mg/kg/week) until resistance ensues. Resistance was defined as continuous tumor growth under cetuximab and an increase in tumor volume of more than 200% compared with baseline. The resistant models were treated continuously with cetuximab without interruption. Cetuximab-resistant PDX were compared with corresponding non-treated (baseline) PDX, with three biological replicates per condition. The study was approved by the ethics committee from UCLouvain (approval ID UCL/MD/2012/09July/314) in accordance with the principles of the Declaration of Helsinki, and all patients gave their written informed consent.