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NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis 1 Introduction 1 Functions of NRG1 and NRG2 2 NRG family 2 Normal physiological functions of NRG1 and NRG2 2 Distribution of NRG1+ and NRG2+ solid malignancies 5 Methods and strategies to detect NRG1 fusions 5 RNA-based NGS 7 WTS and anchor multiple PCR targeted RNA sequencing 7 Differential exon expression (3′/5′ NRG1 ratio; Nanostring) 7 RT-PCR 8 DNA-based NGS 8 Immunohistochemistry (IHC) 9 FISH 9 Clinicopathologic characteristics and screening strategies of NRG fusion positive solid malignancies 10 NRG1+ NSCLC 10 NRG1+ pancreatic ductal adenocarcinoma (PDAC) 10 NRG1+ breast cancer 11 Screening for other NRG1+ solid tumors 11 Potential treatment strategies of NRG1+ solid malignancies 11 Chemotherapy and immune checkpoint inhibitors (ICI) 11 Pan-HER TKIs 13 Afatinib 13 Tarloxotinib 13 Anti HER2/HER3 monoclonal antibodies 13 Zenocutuzumab (MCLA-128) 13 Seribantumab (MM-121, FTN-001), anti HER3 antibody 14 Potential resistance mechanisms to current treatment approaches 14 Concluding remarks and future perspectives 14 Acknowledgments 15 Declaration of interests 15 Resources 15 References

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nonfiction