Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
J Cell Physiol. 2019 Aug;234(8):13137-13144. doi: 10.1002/jcp.27984. Epub 2018 Dec 13.
The human epidermal growth factor 2 (HER2) gene undergoes various mutations that could alter its activity or respond to the antibody therapies. Cetuximab, a known anti-EGFR monoclonal antibody (mAB), is widely administered in metastatic colorectal cancer (mCRC) cases. Here we identified mCRC patients who did not respond to cetuximab (500 mg/m , q2w) after fluoropyrimidine/oxaliplatin regimen failure. Tumor samples were examined with immunohistochemistry for protein distribution, polymerase chain reaction (PCR) sequencing for mutation detection and real-time PCR for mRNA expression pattern analysis between cetuximab sensitive and resistance patients. The conformational differences of normal and mutated protein structures were predicted by bioinformatics analysis. The 5-year survival rates of target groups were estimated using the Kaplan-Meier method. Immunohistochemistry showed that all cases had high level of HER2 protein. No K-Ras or B-Raf mutation was observed among the study population; however, cetuximab resistance patients harbored a somatic mutation R784G at the exon 20 region of HER2 coding sequence. According to bioinformatics analysis, this mutation caused a notable misfold in protein conformation. Meanwhile, survival analysis showed R784G mutated mCRC patients had shortened survival rate compared with the mCRC cases with wild-type HER2. Collectively, these data report a new mechanism of resistance to cetuximab and might be applicable in modifying new therapeutic strategies for HER2 involved cancers.
人类表皮生长因子 2 (HER2) 基因发生多种突变，可能改变其活性或对抗体治疗产生反应。西妥昔单抗，一种已知的抗 EGFR 单克隆抗体（mAB），广泛用于转移性结直肠癌（mCRC）病例。在这里，我们鉴定了氟尿嘧啶/奥沙利铂方案失败后对西妥昔单抗（500mg/m 2 ，q2w）无反应的 mCRC 患者。通过免疫组织化学检测肿瘤样本中蛋白分布，聚合酶链反应（PCR）测序检测突变，实时 PCR 检测敏感和耐药患者的 mRNA 表达模式分析。通过生物信息学分析预测正常和突变蛋白结构的构象差异。使用 Kaplan-Meier 方法估计目标组的 5 年生存率。免疫组织化学显示所有病例均有高水平的 HER2 蛋白。研究人群中未观察到 K-Ras 或 B-Raf 突变；然而，西妥昔单抗耐药患者在 HER2 编码序列的外显子 20 区域携带体细胞突变 R784G。根据生物信息学分析，该突变导致蛋白构象明显错误折叠。同时，生存分析显示 R784G 突变的 mCRC 患者的生存率较野生型 HER2 的 mCRC 患者缩短。总之，这些数据报告了西妥昔单抗耐药的新机制，并可能适用于修改涉及 HER2 的癌症的新治疗策略。
