Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies

SIMPLE SUMMARY: Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second most common cause of cancer-related mortality worldwide. Currently available targeted therapies for metastatic CRC mainly target vascular endothelial growth factor and epidermal growth factor receptor in RAS wild-type tumors. Although Erb-B2 receptor tyrosine kinase 2 (ERBB2/human epidermal growth factor receptor 2) plays a significant therapeutic role in breast and gastric cancers, there are no licensed ERBB2-targeted therapies for metastatic CRC. This review aims to outline the molecular biology of ERBB2-positive metastatic CRC and potential targeted therapeutic strategies. ABSTRACT: Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.