Clinical development of HER3-targeting monoclonal antibodies: Perils and progress

•HER3 is associated with tumor development, resistance and poor clinical prognosis in different cancers.•HER3-targeting agents have been undergoing clinical evaluation for the last 10 years in clinical phase 1 and 2 studies.•Combinations of HER3-binding antibodies with other HER-targeting therapies or chemotherapies have been pursued in various solid tumors.•HER3 and heregulin have been identified as potential response prediction markers.•Inhibition of HER3 has not yet resulted in any meaningful clinical efficacy in the treatment of solid tumors. The human epidermal growth factor receptor (HER) family consists of four transmembrane receptor tyrosine kinases: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. They are part of a complex signalling network and stimulate intracellular pathways regulating cell growth and differentiation. So far, monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors targeting EGFR and HER2 have been developed and approved. Recently, focus has turned to HER3 as it may play an important role in resistance to EGFR- and HER2-targeting therapies. HER3-targeting agents have been undergoing clinical evaluation for the last 10 years and currently thirteen mAbs are in phase 1 or 2 clinical studies. Single agent activity has proven to be limited, however, the tolerability was favourable. Thus, combinations of HER3-binding mAbs with other HER-targeting therapies or chemotherapies have been pursued in various solid tumor entities. Data indicate that the HER3-binding ligand heregulin may serve as a response prediction marker for HER3-targeting therapy. Within this review the current status of clinical development of HER3-targeting compounds is described.