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|Ref Type||Journal Article|
|Authors||Gharib E, Salmanipour R, Nazemalhosseini Mojarad E, Yaghoob Taleghani M, Sarlak S, Malekzade-Moghani M, Nasrabadi PN, Meiary MA, Asadzadeh Aghdaei H, Zali MR|
|Title||HER2+ mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy.|
|Journal||Journal of cellular physiology|
|Date||2018 Dec 13|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|ERBB2||R784G||missense||unknown||ERBB2 (HER2) R784G lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). R784G has been associated with resistance to Egfr antibodies (PMID: 30549033), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 R784G||colorectal cancer||predicted - resistant||Cetuximab||Case Reports/Case Series||Actionable||In a clinical study, ERBB2 R784G was identified in all 11 colorectal cancer patients who were resistant to Erbitux (cetuximab) treatment, and was associated with decreased survival rate (PMID: 30549033).||30549033|