What for patients with NRG1 fusions? Looking into Pandora's box

Neuregulin 1 is a small ligand that interacts with HER2-4 receptors, activating downstream signaling pathways strictly linked to cell survival and proliferation. In some cancers, NRG1 gene is fused with other genes, leading to constitutive activation of the HER signaling and promoting tumorigenesis. Cancers with NRG1 fusions may benefit from pharmacological inhibition using agents that can specifically target either the ligand (NRG1) or the receptor (HER3/HER4), thereby offering a novel personalized approach to therapy by interfering with the growth of cancer cells that depend on this signaling pathway. Multiple strategies are employed to achieve ever-increasing efficacy of the newly proposed therapies, including combination therapies with other targeted approaches, small compounds, and monoclonal antibodies. This narrative review summarizes the available data on the spectrum of all available drugs targeting NRG1/HER deregulation in cancers with NRG1 fusions, their chemistry, pharmacodynamics, pharmacokinetics, and metabolism, as well as the clinical efficacy in NRG1-positive patients.