NRG1 fusion glycoproteins in cancer progression - Structural mechanisms and therapeutic potential: A review.

Neuregulin 1 (NRG1) is a transmembrane glycoprotein ligand of the ErbB receptor family, playing a critical role in macromolecular signaling that regulates cell growth and survival. Chromosomal rearrangements can fuse NRG1 to other genes, creating oncogenic variants that hijack ErbB2/ErbB3 signaling. The resulting chimeric fusion proteins retain the EGF-like domain of NRG1, enabling aberrant dimerization and sustained activation of ErbB2/ErbB3 macromolecular complexes, which in turn activate downstream pathways such as PI3K-AKT and MAPK. This promotes tumor proliferation, survival, and resistance to targeted therapies such as those against EGFR, ALK, and HER2. Despite being rare (incidence <1 %), CD74-NRG1 is the most common fusion. Detection remains challenging due to large intronic regions, making RNA-based next-generation sequencing the most reliable diagnostic method. NRG1-rearranged tumors represent promising therapeutic targets. Current treatments include small-molecule tyrosine kinase inhibitors and bispecific antibodies. However, clinical data largely originate from case reports and early-phase trials. Although NRG1 fusions are increasingly recognized as oncogenic drivers and precision oncology targets, few reviews have fully examined their biological complexities and therapeutic landscape. This review addresses that gap by integrating insights from basic research and clinical practice. We synthesize recent advancements in NRG1-directed therapies, emphasizing clinical trial outcomes and novel treatment strategies. Challenges and emerging opportunities are also discussed to guide future development. Overall, these findings strongly underscore the urgent need for continued investigation into the structural and functional mechanisms of NRG1 fusions and their clinical translation.