Precision Medicine in Metastatic Colorectal Cancer: Targeting ERBB2 (HER-2) Oncogene

Abstract

Colorectal cancer (CRC) is the third most common cancer in terms of incidence rate in adults and the second most common cause of cancer-related death in Europe. The treatment of metastatic CRC (mCRC) is based on the use of chemotherapy, anti-vascular endothelial growth factor (VEGF), and anti-epidermal growth factor receptor (EGFR) for RAS wild-type tumors. Precision medicine tries to identify molecular alterations that could be treated with targeted therapies. ERBB2 amplification (also known as HER-2) has been identified in 2-3% of patients with mCRC, but there are currently no approved ERBB2-targeted therapies for mCRC. The purpose of this review is to describe the molecular structure of ERBB2, clinical features of these patients, diagnosis of ERBB2 alterations, and the most relevant clinical trials with ERBB2-targeted therapies in mCRC.

Keywords: ERBB2; HER-2; colorectal cancer; precision medicine.

Figure 1

Molecular biology of HER2 receptor and mechanisms of action of main available drugs. Activation of HER2 by overexpression (enabling uncontrolled homo- or heterodimerization) or by activating mutations leads to constitutive activation of MAPK, PI-3K/AKT/mTOR, Src, and JAK/STAT pathways. Available drugs block this activation by inhibition of the dimerization or by inhibition of the tyrosine kinase domain of the receptor. T-DM1 and T-Dxd exert their cytopathic effects by liberation of chemotherapy in high concentrations in tumors expressing HER2.