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

针对表皮生长因子受体（EGFR）的单克隆抗体可以成功治疗转移性结直肠癌（mCRC）和头颈部鳞状细胞癌（HNSCC）患者。KRAS （EGFR通路的下游信号分子）的突变预测了mCRC对治疗的反应，因此通常用于患者选择，但目前还没有可用于HNSCC患者选择的标志物。因此，相当一部分HNSCC患者对昂贵的egfr靶向治疗没有反应。越来越多的证据表明，mCRC患者可能在EGFR外域获得耐药介导的突变，破坏西妥昔单抗靶向的表位区域，导致抗体结合丧失，从而丧失临床活性。哪些突变可能获得，它们在egfr靶向治疗下的选择模式以及它们在HNSCC中的潜在作用仍有待阐明。在这项研究中，我们着手通过下一代测序确定40例mCRC患者和40例HNSCC患者的EGFR外域的突变情况，并比较未经治疗的病例和经EGFR靶向治疗的病例的结果。为了研究单个突变的潜在预测价值，结果将与临床对治疗的反应相关联，并将在体外表达选定的突变体，以确定它们与egfr靶向抗体的结合特性。总之，这项研究应该阐明潜在的原发性和继发性耐药机制，并作为长期目标，有助于优化患者对egfr靶向治疗的选择。

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.