Abstract
Human epidermal growth factor receptor 2 (HER2) signaling pathway activation has been identified as a contributor to de novo or acquired resistance to epidermal growth factor receptor (EGFR) inhibitors in a small subset of patients with metastatic colorectal cancer (mCRC). Dual anti-HER2-targeted treatment exhibits strong antitumor activity in preclinical models of HER2-positive mCRC, supporting its testing in clinical trials. The HERACLES trial at four Italian academic cancer centers has confirmed the effectiveness of dual blockage of HER2 with trastuzumab plus lapatinib in patients with heavily pretreated HER2-positive mCRC, refractory to the anti-EGFR antibodies cetuximab or panitumumab. Here, we reviewed the preclinical studies exploring the role of HER2 signaling in the development of anti-EGFR therapy resistance and discussed the status of clinical trials assessing the activity of HER2 inhibitors in this setting.