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HER2 + mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy
Author(s) -
Gharib Ehsan,
Salmanipour Reza,
Nazemalhosseini Mojarad Ehsan,
Yaghoob Taleghani Mohammad,
Sarlak Saharnaz,
MalekzadeMoghani Mona,
Nasrabadi Parinaz Nasri,
Meiary Mohammad Amin,
Asadzadeh Aghdaei Hamid,
Zali Mohammad Reza
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27984
Subject(s) - cetuximab , exon , colorectal cancer , immunohistochemistry , mutation , cancer research , oxaliplatin , population , epidermal growth factor receptor , biology , medicine , oncology , microbiology and biotechnology , cancer , gene , genetics , environmental health
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 2 , 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.