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.

可以用针对表皮生长因子受体（EGFR）的单克隆抗体（EGFR）成功治疗转移性结直肠癌（MCRC）和头颈鳞状细胞癌（HNSCC）的患者。尽管EGFR途径的下游信号分子KRAS中的突变预测了MCRC治疗的反应，因此通常用于患者选择，但目前尚无标记，可用于HNSCC中的患者选择。因此，很大一部分HNSCC患者对昂贵的EGFR靶向方法没有反应。有新兴的证据表明，MCRC患者可能会在EGFR外域中获得耐药性中性突变，该突变破坏了西妥昔单抗靶向的表位区域，从而导致抗体结合损失，从而导致临床活性。可以获取哪些突变，它们在EGFR靶向疗法下的选择模式及其对HNSCC的潜在作用仍有待阐明。在这项研究中，我们着手通过40名患有HNSCC的患者和40例HNSCC患者的Next Generate序列来确定EGFR构域的突变景观，并在未经治疗的情况下进行了均一例子的结果。为了研究单个突变的潜在预测价值，结果将与对治疗的临床反应相关，并且将在体外表达选定的突变体，以确定其与靶向EGFR靶向抗体的结合特性。总的来说，这项研究应阐明潜在的抗药性主要和次要机制，并作为一个长期目标，有助于优化患者选择EGFR靶向疗法。