Characterization of potential resistance-mediating mutations of the EGFR ectodomain in patients with colorectal and head and neck cancer

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Patients with metastatic colorectal cancer (mCRC) and squamous cell carcinoma of the head and neck (HNSCC) can be successfully treated with monoclonal antibodies targeting the epidermal growth factor receptor (EGFR). While mutations in KRAS, a downstream signaling molecule of the EGFR pathway, predicts response to therapy in mCRC and is therefore routinely used for patient selection, there is currently no marker which can be used for patient selection in HNSCC. Therefore a substantial proportion of patients with HNSCC does not respond to the expensive EGFR-targeted approach. There is emerging evidence that mCRC patients may acquire resistance-mediating mutations in the EGFR ectodomain, which destroy the epitope region targeted by cetuximab resulting in loss of antibody binding and therefore clinical activity. Which mutations may be acquired, their pattern of selection under EGFR-targeted therapies and their potential role for HNSCC remains to be elucidated.In this study, we set out to determine the mutational landscape of the EGFR ectodomain by next generation sequencing in 40 patients with mCRC and 40 patients with HNSCC and compare the results from untreated cases with cases after EGFR-targeted therapies. To investigate the potential predictive value of individual mutations, results will be correlated with clinical responses to therapy and selected mutants will be expressed in vitro to determine their binding properties to EGFR-targeting antibodies. Altogether this study should shed light on potential primary and secondary mechanisms of resistance and, as a long-term goal, help to optimize patient selection for EGFR-targeted therapies.