{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:38:33Z","timestamp":1792651113379,"version":"4.5.0"},"reference-count":45,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T00:00:00Z","timestamp":1633737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to unregulated cell proliferation by different mechanisms in a wide variety of cancer. This has led to the development of directed therapies to antagonize a variety of mechanisms that lead to cell growth or proliferation. Multiple oncogene fusions are currently targeted in lung cancer treatment, such as those involving ALK, RET, NTRK and ROS1 among many others. Neuregulin (NRG) gene fusion has been described in the development of normal tissue as well as in a variety of diseases, such as schizophrenia, Hirschsprung\u2019s disease, atrial fibrillation and, most recently, the development of various types of solid tumors, such as renal, gastric, pancreatic, breast, colorectal and, more recently, lung cancer. The mechanism for this is that the NRG1 chimeric ligand leads to aberrant activation of ERBB2 signaling via PI3K-AKT and MAPK cellular cascades, leading to cell division and proliferation. Details regarding the incidence of these gene rearrangements are lacking. Limited case reports and case series have evaluated their clinicopathologic features and prognostic significance in the lung cancer population. Taking this into account, NRG1 could become a targetable alteration in selected patients. This review highlights how the knowledge of new molecular mechanisms of NRG1 fusion may help in gaining new insights into the molecular status of lung cancer patients and unveil a novel targetable molecular marker.<\/jats:p>","DOI":"10.3390\/cancers13205038","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T21:19:32Z","timestamp":1633900772000},"page":"5038","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Neuregulin 1 Gene (NRG1). A Potentially New Targetable Alteration for the Treatment of Lung Cancer"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8909-5760","authenticated-orcid":false,"given":"Daniel","family":"Rosas","sequence":"first","affiliation":[{"name":"The Internal Medicine Department, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5771","authenticated-orcid":false,"given":"Luis E.","family":"Raez","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Program, Memorial Cancer Institute\/Memorial Health Care System, Florida International University (FIU), Miami, FL 33021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3365-1972","authenticated-orcid":false,"given":"Alessandro","family":"Russo","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, A.O Papardo, 981258 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Rolfo","sequence":"additional","affiliation":[{"name":"Clinical Research and Center for Thoracic Oncology, The Tisch Cancer Institute, Mount Sinai Health System & Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2217\/lmt-2017-0018","article-title":"NRG1: A cinderella fusion in lung cancer?","volume":"6","author":"Muscarella","year":"2017","journal-title":"Lung Cancer Manag."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.2174\/0929867324666170911170554","article-title":"NRG1-ErbB Lost in Translation: A New Paradigm for Lung Cancer?","volume":"24","author":"Trombetta","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1158\/1078-0432.CCR-14-0854","article-title":"Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer","volume":"21","author":"Thomas","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4865","DOI":"10.1158\/1078-0432.CCR-19-1219","article-title":"Detection of NRG1 Fusions in Solid Tumors: Rare Gold?","volume":"25","author":"Dimou","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/j.annonc.2020.08.2335","article-title":"NRG1 fusion-driven tumors: Biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents","volume":"31","author":"Laskin","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1158\/1535-7163.MCT-17-1178","article-title":"Dual Targeting of ERBB2\/ERBB3 for the Treatment of SLC3A2-NRG1\u2013Mediated Lung Cancer","volume":"17","author":"Shin","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e161","DOI":"10.1016\/j.jtho.2017.05.014","article-title":"ALK and NRG1 Fusions Coexist in a Patient with Signet Ring Cell Lung Adenocarcinoma","volume":"12","author":"Muscarella","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3166","DOI":"10.21037\/jtd.2018.05.175","article-title":"Neuregulin1 acts as a suppressor in human lung adenocarcinoma via AKT and ERK1\/2 pathway","volume":"10","author":"Wang","year":"2018","journal-title":"J. Thorac. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1177\/1066896917693092","article-title":"KIF13B-NRG1 Gene Fusion and KRAS Amplification in a Case of Natural Progression of Lung Cancer","volume":"25","author":"Xia","year":"2016","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"H443","DOI":"10.1152\/ajpheart.00176.2020","article-title":"The role of endothelial autocrine NRG1\/ERBB4 signaling in cardiac remodeling","volume":"319","author":"Dugaucquier","year":"2020","journal-title":"Am. J. Physiol. Circ. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12887-018-1265-x","article-title":"NRG1 variant effects in patients with Hirschsprung disease","volume":"18","author":"Gunadi","year":"2018","journal-title":"BMC Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.3389\/fphys.2018.01082","article-title":"Regulation of the NRG1\/ErbB4 Pathway in the Intrinsic Cardiac Nervous System Is a Potential Treatment for Atrial Fibrillation","volume":"9","author":"Zhou","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_13","first-page":"1","article-title":"CSF levels of the BACE1 substrate NRG1 correlate with cognition in Alzheimer\u2019s disease","volume":"12","author":"Dumurgier","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/sj.mp.4001817","article-title":"Association of the NRG1 gene and schizophrenia: A meta-analysis","volume":"11","author":"Thiselton","year":"2006","journal-title":"Mol. Psychiatry"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"102363","DOI":"10.1016\/j.ajp.2020.102363","article-title":"Impact of NRG1 HapICE gene variants on digit ratio and dermatoglyphic measures in schizophrenia","volume":"54","author":"Rajasekaran","year":"2020","journal-title":"Asian J. Psychiatry"},{"key":"ref_16","first-page":"1","article-title":"Nrg1 Intracellular Signaling Is Neuroprotective upon Stroke","volume":"2019","author":"Fazzari","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4966","DOI":"10.1158\/1078-0432.CCR-19-0160","article-title":"Detection of NRG1 Gene Fusions in Solid Tumors","volume":"25","author":"Jonna","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1158\/2159-8290.CD-13-0633","article-title":"CD74\u2013NRG1 Fusions in Lung Adenocarcinoma","volume":"4","author":"Plenker","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1053\/j.semnuclmed.2020.06.003","article-title":"The Unmet Needs of the Diagnosis, Staging, and Treatment of Gastrointestinal Tumors","volume":"50","author":"Halama","year":"2020","journal-title":"Semin. Nucl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hegde, G.V., De La Cruz, C., Giltnane, J.M., Crocker, L., Venkatanarayan, A., Schaefer, G., Dunlap, D., Hoeck, J., Piskol, R., and Gnad, F. (2019). NRG1 is a critical regulator of differentiation in TP63-driven squamous cell carcinoma. eLife, 8.","DOI":"10.7554\/eLife.46551"},{"key":"ref_21","first-page":"685","article-title":"NRG1 regulates redox homeostasis via NRF2 in papillary thyroid cancer","volume":"53","author":"Zhang","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1158\/2159-8290.CD-17-1004","article-title":"Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers","volume":"8","author":"Drilon","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.lungcan.2018.07.026","article-title":"EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion","volume":"124","author":"Kim","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13058-020-01377-5","article-title":"NRG1 fusions in breast cancer","volume":"23","author":"Howarth","year":"2021","journal-title":"Breast Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.3892\/ijo.2017.4130","article-title":"NRG1-dependent activation of HER3 induces primary resistance to trastuzumab in HER2-overexpressing breast cancer cells","volume":"51","author":"Yang","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1038\/sj.onc.1208892","article-title":"NRG1 gene rearrangements in clinical breast cancer: Identification of an adjacent novel amplicon associated with poor prognosis","volume":"24","author":"Prentice","year":"2005","journal-title":"Oncogene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"171ra18","DOI":"10.1126\/scitranslmed.3004438","article-title":"Blocking NRG1 and Other Ligand-Mediated Her4 Signaling Enhances the Magnitude and Duration of the Chemotherapeutic Response of Non-Small Cell Lung Cancer","volume":"5","author":"Hegde","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"ref_28","first-page":"7","article-title":"Therapeutic Potential of Afatinib in NRG1 Fusion-Driven Solid Tumors: A Case Series","volume":"26","author":"Cadranel","year":"2021","journal-title":"Oncolology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4674","DOI":"10.1158\/1078-0432.CCR-19-0191","article-title":"NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma","volume":"25","author":"Jones","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10120-017-0732-7","article-title":"Clinical significance of overexpression of NRG1 and its receptors, HER3 and HER4, in gastric cancer patients","volume":"21","author":"Yun","year":"2018","journal-title":"Gastric Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1002\/cam4.838","article-title":"NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma","volume":"5","author":"Duruisseaux","year":"2016","journal-title":"Cancer Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1093\/annonc\/mdx523","article-title":"Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer","volume":"28","author":"Jones","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2791","DOI":"10.1200\/JCO.20.03307","article-title":"Clinicopathologic Features and Response to Therapy of NRG1 Fusion\u2013Driven Lung Cancers: The eNRGy1 Global Multicenter Registry","volume":"39","author":"Drilon","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.2147\/OTT.S78116","article-title":"HGF and NRG1 protein expression are not poor prognostic markers in surgically resected lung adenocarcinoma","volume":"8","author":"Pan","year":"2015","journal-title":"Oncotarget Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"69450","DOI":"10.18632\/oncotarget.11913","article-title":"Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung","volume":"7","author":"Shin","year":"2016","journal-title":"Oncotarget"},{"key":"ref_36","unstructured":"Zensun Sci. & Tech. Co., Ltd. (2021, June 24). A Multi-Center, Randomized, Double-Blined, Placebo Parallel Controlled Phase III Clinical Trial to Evaluate the Effect of Injectable Neucardin on the Mortality of Subjects with Chronic Systolic Heart Failure on Standard HF Therapy\u2013clinicaltrials.gov; 2021, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03388593."},{"key":"ref_37","unstructured":"Zensun Sci. & Tech. Co., Ltd. (2021, June 24). A Multi-Center, Randomized, Double-Blind, Placebo Parallel Controlled, Standard Therapy Based Phase III Clinical Trial to Evaluate the Efficacy and Safety of Recombinant Human Neuregulin-1 for Subcutaneous Administration in Patients with Chronic Systolic Heart Failure\u2013clinicaltrials.gov; 2017, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01214096."},{"key":"ref_38","unstructured":"Zensun Sci. & Tech. Co., Ltd. (2021, June 24). A Phase III, Multi-Center, Randomized, Double-Blind, Based on Standard Therapy, Placebo-Controlled Study of the Efficacy\/Safety of Recombinant Human Neuregulin-1\u03b2 in Patients With Chronic Systolic Heart Failure\u2013clinicaltrials.gov; 2017, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT01439893."},{"key":"ref_39","unstructured":"German Cancer Research Center (2021, June 24). Afatinib in Advanced NRG1-Rearranged Malignancies: The NCT\/DKTK PMO-1604 Phase-II Trial\u2013clinicaltrials.gov; 2021, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04410653."},{"key":"ref_40","unstructured":"Shun, L. (2021, June 24). An Open-Labeled, Single-Arm Clinical Study to Evaluate the Efficacy of Afatinib in Treatment of Locally Advanced or Metastatic Non-Small Cell Lung Cancer with NRG1-Fusion\u2013clinicaltrials.gov; 2021, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04814056."},{"key":"ref_41","unstructured":"Ottawa Hospital Research Institute (2021, June 24). Single Patient Protocol for an NRG1 Fusion Positive Metastatic Pancreatic Cancer Patient Using Seribantumab\u2013clinicaltrials.gov; 2021, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04790695."},{"key":"ref_42","unstructured":"Elevation Oncology (2021, June 24). CRESTONE: A Phase 2 Study of Seribantumab in Adult Patients with Neuregulin-1 (NRG1) Fusion Positive Locally Advanced or Metastatic Solid Tumors\u2013clinicaltrials.gov; 2021, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04383210."},{"key":"ref_43","unstructured":"Rain Therapeutics Inc. (2021, June 24). Phase 2 Study\u2013Evaluate the Clinical Activity of Tarloxotinib in Patients with Non-Small Cell Lung Cancer That Harbors an EGFR Exon 20 Insertion or HER2-Activating Mutation and Other Advanced Solid Tumors with NRG1\/ERBB Family Gene Fusions\u2013clinicaltrials.gov; 2020, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03805841."},{"key":"ref_44","unstructured":"Merus, N.V. (2021, June 24). A Phase I\/II Study of MCLA-128, a Full Length IgG1 Bispecific Antibody Targeting HER2 and HER3, in Patients with Solid Tumors\u2013clinicaltrials.gov; 2021, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02912949."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.1200\/JCO.2021.39.15_suppl.3003","article-title":"Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions","volume":"39","author":"Schram","year":"2021","journal-title":"J. Clin. Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/20\/5038\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:10:50Z","timestamp":1760166650000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/20\/5038"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,9]]},"references-count":45,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["cancers13205038"],"URL":"https:\/\/doi.org\/10.3390\/cancers13205038","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,9]]}}}