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Ref Type Journal Article
PMID (30549033)
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
Vol
Issue
Date 2018 Dec 13
URL
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.

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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