HER2+ mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy |
| |
Authors: | Ehsan Gharib Reza Salmanipour Ehsan Nazemalhosseini Mojarad Mohammad Yaghoob Taleghani Saharnaz Sarlak Mona Malekzade-Moghani Parinaz Nasri Nasrabadi Mohammad Amin Meiary Hamid Asadzadeh Aghdaei Mohammad Reza Zali |
| |
Institution: | 1. Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran;2. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran;3. Department of Radiation Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran |
| |
Abstract: | 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/m2, 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. |
| |
Keywords: | cetuximab therapy failure HER2 somatic mutation metastatic colorectal cancer |
|
|