HER2⁺ mCRC patients with exon 20 R784G substitution mutation do not respond to the cetuximab therapy

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.

The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as well as Pertuzumab

“…Patients with the HER2 L755S mutation were resistant to trastuzumab and lapatinib treatment, and a non-small cell lung cancer patient with HER2 N813D mutations was resistant to afatinib [61,62]. HER2 positive metastatic colorectal cancer patients with HER2 T784G mutation did not respond to cetuximab therapy [63]. A recent study showed that cells with the HER2 L755S mutation were resistant to lapatinib [64].…”

Liquid biopsy to detect resistance mutations against anti-epidermal growth factor receptor therapy in metastatic colorectal cancer

“…Although most HER2-based studies have primarily focused on breast cancer, the role of this receptor in mCRC has recently been described[ 63 , 64 ]. Previous in vitro and prospective patient studies have suggested that both the presence of mutations related to the active site of the receptor and HER2 amplification are associated with a poor response to anti-EGFR therapy[ 62 , 63 , 65 ]. In addition, the acquisition of mutations in HER2 may be an underlying mechanism of secondary resistance that can be detected early using liquid biopsy.…”

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

“…The HERACLES trials showed that ERBB2 inhibitors are an emerging treatment option in CRC [ 117 ]. It has been described that high ERBB2 expression levels detected by immunohistochemistry were associated with cetuximab resistance in metastatic CRC and that the presence of the R784G mutation, which lies within the protein kinase domain of the protein, correlated with lower survival rate [ 118 ].…”