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

结直肠癌和头颈癌患者 EGFR 胞外域潜在耐药介导突变的特征

• 批准号: 243019617
• 负责人: Professorin Dr. Mascha Binder, Ph.D.
• 金额: --
• 依托单位: Departement Biomedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/243019617?language=en
• 关键词: Characterization; potential; resistance; mediating; mutations

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.

转移性结直肠癌（mCRC）和头颈部鳞状细胞癌（HNSCC）患者可以成功地用靶向表皮生长因子受体（EGFR）的单克隆抗体治疗。虽然EGFR通路下游信号分子KRAS的突变可预测mCRC对治疗的应答，因此通常用于患者选择，但目前尚无可用于HNSCC患者选择的标志物。因此，相当大比例的HNSCC患者对昂贵的EGFR靶向方法没有反应。有新的证据表明，mCRC患者可能在EGFR胞外域获得耐药介导突变，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。哪些突变可能被获得，EGFR靶向治疗的选择模式及其对HNSCC的潜在作用仍有待阐明，在这项研究中，我们通过下一代测序确定了40例mCRC和40例HNSCC患者EGFR胞外域的突变情况，并将未经治疗的病例与EGFR靶向治疗后的病例的结果进行了比较。为了研究单个突变的潜在预测价值，将结果与对治疗的临床反应相关联，并将在体外表达选定的突变体以确定其与EGFR靶向抗体的结合特性。总之，这项研究应该阐明潜在的主要和次要耐药机制，并作为一个长期目标，有助于优化EGFR靶向治疗的患者选择。