Neuregulin 1 Fusion–Positive NSCLC
Authors: Misako Nagasaka, Sai-Hong Ignatius Ou
Journal: Journal of Thoracic Oncology (2019)

In the past decade, we have witnessed the identification of multiple actionable driver mutations in NSCLC encompassing the four major modes of genetic alterations: point mutations, insertions/deletions (indels), gene amplification, and gene fusions primarily involving receptor tyrosine kinase (RTK) receptors.1Tsao A.S. Scagliotti G.V. Bunn Jr., P.A. et al.Scientific advances in lung cancer 2015.J Thorac Oncol. 2016; 11: 613-638Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar In 2014, the first neuregulin 1 (NRG1) fusion in NSCLC was reported by Fernandez-Cuesta et al.2Fernandez-Cuesta L. Plenker D. Osada H. et al.CD74-NRG1 fusions in lung adenocarcinoma.Cancer Discov. 2014; 4: 415-422Crossref PubMed Scopus (192) Google Scholar when they identified five CD74-NRG1 fusions in invasive mucinous adenocarcinoma (IMA) of the lung. Physiologically, NRG1 is proteolytically cleaved and secreted and is involved in the diverse spectrum of cellular process primarily but not limited to neural development.3Willem M. Proteolytic processing of neuregulin-1.Brain Res Bull. 2016; 126: 178-182Google Scholar The CD74-NRG1 fusion provides an extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to erb-b2 receptor tyrosine kinase 3 (HER3) leading to HER3 heterodimerization and activation of downstream signaling pathways leading to oncogenesis.4Fernandez-Cuesta L. Thomas R.K. Molecular pathways: targeting NRG1 fusions in lung cancer.Clin Cancer Res. 2015; 21: 1989-1994Crossref PubMed Scopus (51) Google Scholar NRG1 fusions thus represent a novel mechanism of generating ligand proximity to the natural occurring wild-type RTKs that is distinct from the oligomerization of rearranged RTK kinase domains we are now familiar with.5Schram A.M. Chang M.T. Jonsson P. Drilon A. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance.Nat Rev Clin Oncol. 2017; 14: 735-748Crossref PubMed Scopus (189) Google Scholar Overall, NRG1 fusions are relatively rare. The incidence of NRG1+ fusions is estimated to be at 0.2% (41 positive cases) from a recent large scale survey of 21,858 cases of solid malignancies using RNA sequencing which is generally considered to be the gold standard to dettect rare gene fusions. Although the vast majority of the NRG1+ fusion cases are found in NSCLC (61%, 25 of 41), NRG1+ NSCLC only constitutes 0.3% of all NSCLC samples tested.6Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar After the initial report of CD74-NRG1 NSCLC, three more groups in rapid succession all reported the identification of NRG1 fusions in NSCLC and extended the NRG1 fusions variants to solute carrier family 3 member 2 (SLC3A2)–NRG1, syndecan 4 (SDC4)–NRG1, RNA binding protein, mRNA processing factor (RBPMS)–NRG1, and WRN RecQ like helicase (WRN)–NRG1 in 2014.7Nakaoku T. Tsuta K. Ichikawa H. et al.Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.Clin Cancer Res. 2014; 20: 3087-3093Crossref PubMed Scopus (153) Google Scholar, 8Gow C.H. Wu S.G. Chang Y.L. et al.Multidriver mutation analysis in pulmonary mucinous adenocarcinoma in Taiwan: identification of a rare CD74-NRG1 translocation case.Med Oncol. 2014; 31: 34Crossref PubMed Scopus (22) Google Scholar, 9Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar The identification of WRN-NRG1 extended the presence of NRG1 fusion to squamous cell lung cancer.9Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar To date, there are 17 fusion partners identified in NRG1+ NSCLC (Table 1) with the CD74-NRG1 fusion variant as the most common in NSCLC followed by SLC3A2-NRG1 and SDC4-NRG1 (Fig. 1A) in published literature.2Fernandez-Cuesta L. Plenker D. Osada H. et al.CD74-NRG1 fusions in lung adenocarcinoma.Cancer Discov. 2014; 4: 415-422Crossref PubMed Scopus (192) Google Scholar, 6Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar, 7Nakaoku T. Tsuta K. Ichikawa H. et al.Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.Clin Cancer Res. 2014; 20: 3087-3093Crossref PubMed Scopus (153) Google Scholar, 8Gow C.H. Wu S.G. Chang Y.L. et al.Multidriver mutation analysis in pulmonary mucinous adenocarcinoma in Taiwan: identification of a rare CD74-NRG1 translocation case.Med Oncol. 2014; 31: 34Crossref PubMed Scopus (22) Google Scholar, 9Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar, 10Shim H.S. Kenudson M. Zheng Z. et al.Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung.J Thorac Oncol. 2015; 10: 1156-1162Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 11Jung Y. Yong S. Kim P. et al.VAMP2-NRG1 fusion gene is a novel oncogenic driver of non–small-cell lung adenocarcinoma.J Thorac Oncol. 2015; 10: 1107-1111Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 12Xia D. Le L.P. Iafrate A.J. et al.KIF13B-NRG1 gene fusion and KRAS amplification in a case of natural progression of lung cancer.Int J Surg Pathol. 2017; 25: 238-240Google Scholar, 13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar, 14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google Scholar, 15Duruisseaux M. McLeer-Florin A. Antoine M. et al.NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.Cancer Med. 2016; 5: 3579-3585Crossref PubMed Scopus (27) Google Scholar, 16Trombetta D. Graziano P. Scarpa A. et al.Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression.Oncotarget. 2018; 9: 9661-9671Google Scholar, 17Wang R. Zhang Y. Pan Y. et al.Comprehensive investigation of oncogenic driver mutations in Chinese non–small cell lung cancer patients.Oncotarget. 2015; 6: 34300-34308Crossref PubMed Scopus (67) Google Scholar, 18Sunami K. Furuta K. Tsuta K. et al.Multiplex diagnosis of oncogenic fusion and MET exon skipping by molecular counting using formalin-fixed paraffin embedded lung adenocarcinoma tissues.J Thorac Oncol. 2016; 11: 203-212Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 19Muscarella L.A. Trombetta D. Fabrizio F.P. et al.ALK and NRG1 fusions coexist in a patient with signet ring cell lung adenocarcinoma.J Thorac Oncol. 2017; 12: e161-e163Abstract Full Text Full Text PDF Scopus (14) Google Scholar, 20Gay N.D. Wang Y. Beadling C. et al.Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions.J Thorac Oncol. 2017; 12: e107-e110Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 21Jones M.R. Lim H. Shen Y. et al.Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.Ann Oncol. 2017; 28: 3092-3097Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 22Cheema P.K. Doherty M. Tsao M.S. A case of invasive mucinous pulmonary adenocarcinoma with a CD74-NRG1 fusion protein targeted with afatinib.J Thorac Oncol. 2017; 12: e200-e202Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 23Kim H.S. Han J.Y. Shin D.H. et al.EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion.Lung Cancer. 2018; 124: 71-75Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar It is important to note that many of the fusion partners identified in other non-NSCLC NRG1+ solid tumors by Jonna and colleagues remained to be identified in NRG1+ NSCLC. Hence the number of NRG1+ NSCLC fusion partners is sure to increase in the future.6Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar Of note, among the 15 SLC3A2-NRG1 fusions reported in the literature so far, 13 were identified in Asian patients (12 from Korea, and 1 from Japan). The majority of the patients with NRG1+ NSCLC had IMA histology with squamous cell carcinoma hisology (LUSC) accounting for 6% (Fig. 1B). 2Fernandez-Cuesta L. Plenker D. Osada H. et al.CD74-NRG1 fusions in lung adenocarcinoma.Cancer Discov. 2014; 4: 415-422Crossref PubMed Scopus (192) Google Scholar, 6Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar, 7Nakaoku T. Tsuta K. Ichikawa H. et al.Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.Clin Cancer Res. 2014; 20: 3087-3093Crossref PubMed Scopus (153) Google Scholar, 8Gow C.H. Wu S.G. Chang Y.L. et al.Multidriver mutation analysis in pulmonary mucinous adenocarcinoma in Taiwan: identification of a rare CD74-NRG1 translocation case.Med Oncol. 2014; 31: 34Crossref PubMed Scopus (22) Google Scholar, 9Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar, 10Shim H.S. Kenudson M. Zheng Z. et al.Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung.J Thorac Oncol. 2015; 10: 1156-1162Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 11Jung Y. Yong S. Kim P. et al.VAMP2-NRG1 fusion gene is a novel oncogenic driver of non–small-cell lung adenocarcinoma.J Thorac Oncol. 2015; 10: 1107-1111Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 12Xia D. Le L.P. Iafrate A.J. et al.KIF13B-NRG1 gene fusion and KRAS amplification in a case of natural progression of lung cancer.Int J Surg Pathol. 2017; 25: 238-240Google Scholar, 13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar, 14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google Scholar, 15Duruisseaux M. McLeer-Florin A. Antoine M. et al.NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.Cancer Med. 2016; 5: 3579-3585Crossref PubMed Scopus (27) Google Scholar, 16Trombetta D. Graziano P. Scarpa A. et al.Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression.Oncotarget. 2018; 9: 9661-9671Google Scholar, 17Wang R. Zhang Y. Pan Y. et al.Comprehensive investigation of oncogenic driver mutations in Chinese non–small cell lung cancer patients.Oncotarget. 2015; 6: 34300-34308Crossref PubMed Scopus (67) Google Scholar, 18Sunami K. Furuta K. Tsuta K. et al.Multiplex diagnosis of oncogenic fusion and MET exon skipping by molecular counting using formalin-fixed paraffin embedded lung adenocarcinoma tissues.J Thorac Oncol. 2016; 11: 203-212Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 19Muscarella L.A. Trombetta D. Fabrizio F.P. et al.ALK and NRG1 fusions coexist in a patient with signet ring cell lung adenocarcinoma.J Thorac Oncol. 2017; 12: e161-e163Abstract Full Text Full Text PDF Scopus (14) Google Scholar, 20Gay N.D. Wang Y. Beadling C. et al.Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions.J Thorac Oncol. 2017; 12: e107-e110Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 21Jones M.R. Lim H. Shen Y. et al.Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.Ann Oncol. 2017; 28: 3092-3097Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 22Cheema P.K. Doherty M. Tsao M.S. A case of invasive mucinous pulmonary adenocarcinoma with a CD74-NRG1 fusion protein targeted with afatinib.J Thorac Oncol. 2017; 12: e200-e202Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 23Kim H.S. Han J.Y. Shin D.H. et al.EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion.Lung Cancer. 2018; 124: 71-75Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar The majority of patients with NRG1+ NSCLC with known smoking status were never-smokers, but smoking status in many patients with NRG1+ NSCLC was not reported (Fig. 1C). 2Fernandez-Cuesta L. Plenker D. Osada H. et al.CD74-NRG1 fusions in lung adenocarcinoma.Cancer Discov. 2014; 4: 415-422Crossref PubMed Scopus (192) Google Scholar, 6Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar, 7Nakaoku T. Tsuta K. Ichikawa H. et al.Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.Clin Cancer Res. 2014; 20: 3087-3093Crossref PubMed Scopus (153) Google Scholar, 8Gow C.H. Wu S.G. Chang Y.L. et al.Multidriver mutation analysis in pulmonary mucinous adenocarcinoma in Taiwan: identification of a rare CD74-NRG1 translocation case.Med Oncol. 2014; 31: 34Crossref PubMed Scopus (22) Google Scholar, 9Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar, 10Shim H.S. Kenudson M. Zheng Z. et al.Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung.J Thorac Oncol. 2015; 10: 1156-1162Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 11Jung Y. Yong S. Kim P. et al.VAMP2-NRG1 fusion gene is a novel oncogenic driver of non–small-cell lung adenocarcinoma.J Thorac Oncol. 2015; 10: 1107-1111Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 12Xia D. Le L.P. Iafrate A.J. et al.KIF13B-NRG1 gene fusion and KRAS amplification in a case of natural progression of lung cancer.Int J Surg Pathol. 2017; 25: 238-240Google Scholar, 13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar, 14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google Scholar, 15Duruisseaux M. McLeer-Florin A. Antoine M. et al.NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.Cancer Med. 2016; 5: 3579-3585Crossref PubMed Scopus (27) Google Scholar, 16Trombetta D. Graziano P. Scarpa A. et al.Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression.Oncotarget. 2018; 9: 9661-9671Google Scholar, 17Wang R. Zhang Y. Pan Y. et al.Comprehensive investigation of oncogenic driver mutations in Chinese non–small cell lung cancer patients.Oncotarget. 2015; 6: 34300-34308Crossref PubMed Scopus (67) Google Scholar, 18Sunami K. Furuta K. Tsuta K. et al.Multiplex diagnosis of oncogenic fusion and MET exon skipping by molecular counting using formalin-fixed paraffin embedded lung adenocarcinoma tissues.J Thorac Oncol. 2016; 11: 203-212Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 19Muscarella L.A. Trombetta D. Fabrizio F.P. et al.ALK and NRG1 fusions coexist in a patient with signet ring cell lung adenocarcinoma.J Thorac Oncol. 2017; 12: e161-e163Abstract Full Text Full Text PDF Scopus (14) Google Scholar, 20Gay N.D. Wang Y. Beadling C. et al.Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions.J Thorac Oncol. 2017; 12: e107-e110Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 21Jones M.R. Lim H. Shen Y. et al.Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.Ann Oncol. 2017; 28: 3092-3097Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 22Cheema P.K. Doherty M. Tsao M.S. A case of invasive mucinous pulmonary adenocarcinoma with a CD74-NRG1 fusion protein targeted with afatinib.J Thorac Oncol. 2017; 12: e200-e202Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 23Kim H.S. Han J.Y. Shin D.H. et al.EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion.Lung Cancer. 2018; 124: 71-75Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In one report, the presence of NRG1 fusions confers a poor survival among mucinous lung adenocarcinoma.14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google ScholarTable 1List of NRG1 Fusion Partners Identified in NSCLCNumberFusion PartnerNRG1 Fusion BreakpointReferenceaThe reference(s) that describes the fusion variant first is listed.1CD74CD74-NRG1 (C6, N6)Fernandez-Cuesta et al., 20142Fernandez-Cuesta L. Plenker D. Osada H. et al.CD74-NRG1 fusions in lung adenocarcinoma.Cancer Discov. 2014; 4: 415-422Crossref PubMed Scopus (192) Google Scholar2SLC3A2SLC3A2-NRG1 (S5, N6)Nakaoku et al., 20147Nakaoku T. Tsuta K. Ichikawa H. et al.Druggable oncogene fusions in invasive mucinous lung adenocarcinoma.Clin Cancer Res. 2014; 20: 3087-3093Crossref PubMed Scopus (153) Google Scholar3SDC4-NRG1SDC4-NRG1 (S4, N6)Dhanasekaran et al., 20149Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar4RBPMSRBPMS-NRG1 (R6, N6)Dhanasekaran et al., 20149Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar5WRNWRN-NRG1 (WRN 5'UTR, N1)Dhanasekaran et al., 20149Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar6VAMP2VAMP2-NRG1 (V4, N5)Shim et al., 201510Shim H.S. Kenudson M. Zheng Z. et al.Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung.J Thorac Oncol. 2015; 10: 1156-1162Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar; Jung et al., 201511Jung Y. Yong S. Kim P. et al.VAMP2-NRG1 fusion gene is a novel oncogenic driver of non–small-cell lung adenocarcinoma.J Thorac Oncol. 2015; 10: 1107-1111Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar7KIF13BKIF13B-NRG1 (K2, N2)Xia et al., 201712Xia D. Le L.P. Iafrate A.J. et al.KIF13B-NRG1 gene fusion and KRAS amplification in a case of natural progression of lung cancer.Int J Surg Pathol. 2017; 25: 238-240Google Scholar8SMAD4SMAD4-NRG1 (S1, N6)Drilon et al., 201813Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar9THAP7THAP7-NRG1 (T6, N6)Drilon et al., 201813Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar10MDKMDK-NRG1 (M4, N6)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar11TNCTNC-NRG1 (T10, N6)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar12ATP1B1ATP1B1-NRG1 (A2, N2)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar13DIP2BDIP2B-NRG1 (D1, N2)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar14MRPL13MRPL13-NRG1 (M2, N2)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar15PARP8PARP8-NRG1 (P1, N2)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar16ROCK1ROCK1-NRG1 (R1, N2)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar17DPYSL2DPYSL2-NRG1 (D7, N5)Jonna et al., 20196Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholara The reference(s) that describes the fusion variant first is listed. Open table in a new tab Figure 1(A) Pie-chart of the proportion of each fusion partner identified in NRG1+ NSCLC reported in the literature. A total of 99 NRG1+ NSCLC cases were identified in the literature and included: CD74 (n = 47), SLC3A2 (n = 16), unknown (n = 13), SDC4 (n = 7), RBPMS (n = 2), VAMP2 (n = 2), ATP1B1, DIP2B, DPYSL2, KIF13B, MDK, MRPL13, PARP8, ROCK1, SMAD4, THAP7, TNC, and WRN (all n = 1). (B) Pie-chart of the histology of the 99 patients with NRG1+ NSCLC. Invasive mucinous adenocarcinoma (IMA) (n = 61), adenocarcinoma not otherwise specific (AdenoCA NOS) (n = 29), AdenoCA, papillary (n = 2), AdenoCA, acinar (n = 1), squamous cell carcinoma (SqCC, n = 6), other (N = 1). (C) Pie-chart of the smoking status of the NRG1+ NSCLC cases. Never-smoker (n = 30), ever-smoker (n = 12), and unknown (n = 57).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Given the rarity of NRG1+ NSCLC, a basic understanding of the genomic structure of the NRG1 will help our appreciation of the potential complexities in detecting NRG1+ NSCLC. There are three major NRG1 isoforms (type I [heregulin], II [glial growth factor-2 (GGF2)], and III [sensory and motor neuron-derived factor (SMDF)]) and potentially six minor NRG1 isoforms which have unique function and organ-specific expression.3Willem M. Proteolytic processing of neuregulin-1.Brain Res Bull. 2016; 126: 178-182Google Scholar, 24Steinthorsdottir V. Stefansson H. Ghosh S. et al.Multiple novel transcription initiation sites for NRG1.Gene. 2004; 342: 97-105Crossref PubMed Scopus (129) Google Scholar, 25Falls D.L. Neuregulins: functions, forms, and signaling strategies.Exp Cell Res. 2003; 284: 14-30Crossref PubMed Scopus (852) Google Scholar For example, type I NRG1 is translated into a transmembrane protein which is then proteolytically cleaved releasing the EGF-containing portion of NRG1 into the cytoplasm.3Willem M. Proteolytic processing of neuregulin-1.Brain Res Bull. 2016; 126: 178-182Google Scholar, 24Steinthorsdottir V. Stefansson H. Ghosh S. et al.Multiple novel transcription initiation sites for NRG1.Gene. 2004; 342: 97-105Crossref PubMed Scopus (129) Google Scholar, 25Falls D.L. Neuregulins: functions, forms, and signaling strategies.Exp Cell Res. 2003; 284: 14-30Crossref PubMed Scopus (852) Google Scholar The EGF motif is located extracellularly very close to the transmembrane region (Fig. 2A).24Steinthorsdottir V. Stefansson H. Ghosh S. et al.Multiple novel transcription initiation sites for NRG1.Gene. 2004; 342: 97-105Crossref PubMed Scopus (129) Google Scholar, 25Falls D.L. Neuregulins: functions, forms, and signaling strategies.Exp Cell Res. 2003; 284: 14-30Crossref PubMed Scopus (852) Google Scholar The type-specific exons are located at various 5' regions of the NRG1 gene (Figs. 2A and B).24Steinthorsdottir V. Stefansson H. Ghosh S. et al.Multiple novel transcription initiation sites for NRG1.Gene. 2004; 342: 97-105Crossref PubMed Scopus (129) Google Scholar, 25Falls D.L. Neuregulins: functions, forms, and signaling strategies.Exp Cell Res. 2003; 284: 14-30Crossref PubMed Scopus (852) Google Scholar DNA breakpoints in NRG1 fusions have been identified within the 111 kilobase (kb) intronic regions between exon s2 (exon 5) and exon EGFc (exon 6), which also contains the type III–specific exon (Fig. 2A), and between the type I– and type II–specific exon and the exon Ig1 (exon 2).24Steinthorsdottir V. Stefansson H. Ghosh S. et al.Multiple novel transcription initiation sites for NRG1.Gene. 2004; 342: 97-105Crossref PubMed Scopus (129) Google Scholar, 25Falls D.L. Neuregulins: functions, forms, and signaling strategies.Exp Cell Res. 2003; 284: 14-30Crossref PubMed Scopus (852) Google Scholar The intronic region spans 47 kb between type 1–specific exon (Fig. 2A) and exon 2, and spans 955 kb for type II–specific exon and exon 2 (Fig. 2B).24Steinthorsdottir V. Stefansson H. Ghosh S. et al.Multiple novel transcription initiation sites for NRG1.Gene. 2004; 342: 97-105Crossref PubMed Scopus (129) Google Scholar, 25Falls D.L. Neuregulins: functions, forms, and signaling strategies.Exp Cell Res. 2003; 284: 14-30Crossref PubMed Scopus (852) Google Scholar These two large intronic regions (111.0 kb and 995.2 kb) where DNA rearrangement occurs to generate NRG1 fusions implies that RNA sequencing should be more sensitive in detecting these rare NRG1 fusions than hybrid DNA capture sequencing approach which will need to use DNA probes to span these two large intronic regions to identify the DNA breakpoints or known NRG1+ fusion partners which currenrly stands at 17 for NRG1+ NSCLC. Indeed, Drilon et al.13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar identified seven additional NRG1+ solid tumor fusion variants (6 NRG1+ NSCLC) with RNA sequencing in addition to the MSKCC-IMPACT DNA sequencing approach. Fluorescence in situ hybridization (FISH) has been successfully used as the primary method to identify NRG1+ NSCLC but the specific fusion partners were unknown in many of NRG1 FISH positive cases.14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google Scholar, 15Duruisseaux M. McLeer-Florin A. Antoine M. et al.NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.Cancer Med. 2016; 5: 3579-3585Crossref PubMed Scopus (27) Google Scholar In terms of using immunohistochemistry (IHC) to screen and detect NRG1+ NSCLC in patients, Fernandez-Cuesta et al.2Fernandez-Cuesta L. Plenker D. Osada H. et al.CD74-NRG1 fusions in lung adenocarcinoma.Cancer Discov. 2014; 4: 415-422Crossref PubMed Scopus (192) Google Scholar showed that phospho-HER3 (p-ERBB3) IHC reported a sensitivity of 100% and a specificity of 97.5% among 245 lung adenocarcinoma samples. p-ERBB3 IHC also had a sensitivity of 94% and a specificity of 100% among 51 IMA samples and 100% sensitivity and 94% specificity among 34 non-IMA adenocarcinoma samples when using FISH as the method for comparison.16Trombetta D. Graziano P. Scarpa A. et al.Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression.Oncotarget. 2018; 9: 9661-9671Google Scholar The majority of NRG1+ NSCLC cases have IMA histology (Fig. 1B), but IMA accounts for only 5% of lung adenocarcinoma.26Cha Y.J. Shim H.S. Biology of invasive mucinous adenocarcinoma of the lung.Transl Lung Cancer Res. 2017; 6: 508-512Crossref PubMed Scopus (45) Google Scholar Furthermore, KRAS mutations as a whole account for ∼ 60% whereas NRG1+ fusions account for ∼7% of IMAs of the lung.26Cha Y.J. Shim H.S. Biology of invasive mucinous adenocarcinoma of the lung.Transl Lung Cancer Res. 2017; 6: 508-512Crossref PubMed Scopus (45) Google Scholar NRG1 fusion is generally mutually exclusive of other driver mutations and KRAS mutations6Jonna S. Feldman R.A. Swensen J. et al.Detection of NRG1 fusions in solid tumors.Clin Cancer Res. 2019; https://doi.org/10.1158/1078-0432.CCR-19-0160Crossref Scopus (98) Google Scholar, 13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar; however, the finding of exclusivity between KRAS mutations and NRG1 fusion is not universally observed.14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google Scholar A screening approach of p-ERBB3 IHC in lung adenocarcinoma and definitely in IMA followed by RNA sequencing may be the optimal and cost-effective approach to identify these extremely rare NRG1+ NSCLC cases. Nevertheless, we have to bear in mind that WRN-NRG1, SDC4-NRG1, and THAP domain containing 7 (THAP7)–NRG1 have been identified in LUSC and LUSC accounts for 6% of all NRG1+ NSCLC histologies reported in the literature (Fig. 1B).8Gow C.H. Wu S.G. Chang Y.L. et al.Multidriver mutation analysis in pulmonary mucinous adenocarcinoma in Taiwan: identification of a rare CD74-NRG1 translocation case.Med Oncol. 2014; 31: 34Crossref PubMed Scopus (22) Google Scholar, 9Dhanasekaran S.M. Balbin O.A. Chen G. et al.Transcriptome meta-analysis of lung cancer reveals recurrent aberrations in NRG1 and Hippo pathway genes.Nat Commun. 2014; 5: 5893Crossref PubMed Scopus (112) Google Scholar, 13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar Patients who have NRG1+ NSCLC have been treated with afatinib that inhibits the kinase activity of EGFR/HER2 or HER3 monoclonal antibodies that can block ligand-dependent activation of HER3 and subsequent hetero-dimerization with EGFR, HER2, and HER4 with mixed success (Table 2).13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar, 14Shin D.H. Lee D. Hong D.W. et al.Oncogenic function and clinical implications of SLC3A2-NRG1 fusion in invasive mucinous adenocarcinoma of the lung.Oncotarget. 2016; 7: 69450-69465Crossref PubMed Scopus (46) Google Scholar, 15Duruisseaux M. McLeer-Florin A. Antoine M. et al.NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.Cancer Med. 2016; 5: 3579-3585Crossref PubMed Scopus (27) Google Scholar, 16Trombetta D. Graziano P. Scarpa A. et al.Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression.Oncotarget. 2018; 9: 9661-9671Google Scholar, 17Wang R. Zhang Y. Pan Y. et al.Comprehensive investigation of oncogenic driver mutations in Chinese non–small cell lung cancer patients.Oncotarget. 2015; 6: 34300-34308Crossref PubMed Scopus (67) Google Scholar Drilon et al.13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar reported one patient with NRG1+ NSCLC achieving the longest duration of response among all of the case reports (19 months) with an anti-HER3 monoclonal antibody that both inhibit NRG1 binding to HER3 and HER3 heterodimerization and can mediate antibody-dependent cellular cytotoxicity.13Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar, 27Malm M. Frejd F.Y. Ståhl S. Löfblom J. Targeting HER3 using mono- and bispecific antibodies or alternative scaffolds.MAbs. 2016; 8: 1195-1209Crossref PubMed Scopus (31) Google Scholar, 28Jacob W. James I. Hasmann M. Weisser M. Clinical development of HER3-targeting monoclonal antibodies: perils and progress.Cancer Treat Rev. 2018; 68: 111-123Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Many monoclonal mono- (HER3) or bi-specific HER2/HER3 monoclonal antibodies are in clinical development that could potentially be used to target NRG1+ fusions.27Malm M. Frejd F.Y. Ståhl S. Löfblom J. Targeting HER3 using mono- and bispecific antibodies or alternative scaffolds.MAbs. 2016; 8: 1195-1209Crossref PubMed Scopus (31) Google Scholar, 28Jacob W. James I. Hasmann M. Weisser M. Clinical development of HER3-targeting monoclonal antibodies: perils and progress.Cancer Treat Rev. 2018; 68: 111-123Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Additionally, tarloxotinib, an irreversible pan-HER inhibiting prodrug that is selectively activated under hypoxic conditions has shown to inhibit cell lines and patient-derived xenografts harboring NRG1 fusions (DOC4-NRG1 and clusterin [CLU]–NRG1, respectively).29Tirunagaru VG, Estrada-Bernal A, Yu H, et al. Tarloxotinib exhibits potent activity in NRG1 fusion and rearranged cancers. Paper presented at: AACR Annual Meeting 2019. March 29-April 3, 2019; Atlanta, Georgia (abstract #2202).Google Scholar Tarloxotinib is in the process of enrolling patients with NRG1+ tumors (NCT03805841).Table 2List of Case Reports on the Outcomes of Inhibiting HER2/HER3 Signaling Pathway in NRG1+ NSCLC Reported in the LiteratureaIncludes one case of NRG1+ intrahepatic cholangiocarcinoma (case 4).CaseAgeSexNRG1 Fusions VariantSolid MalignanciesTreatment ModalityDuration of ResponseReferences142MSLC3A2-NRG1LUACAfatinib 40 mg daily12 moGay et al., 201720Gay N.D. Wang Y. Beadling C. et al.Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions.J Thorac Oncol. 2017; 12: e107-e110Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar262MCD74-NRG1LUAC (mucinous)Afatinib 40 mg daily10 moGay et al., 201720Gay N.D. Wang Y. Beadling C. et al.Durable response to afatinib in lung adenocarcinoma harboring NRG1 gene fusions.J Thorac Oncol. 2017; 12: e107-e110Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar343FSDC4-NRG1LUACAfatinib 30 mg daily12 moJones et al., 201721Jones M.R. Lim H. Shen Y. et al.Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.Ann Oncol. 2017; 28: 3092-3097Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar438FATP1B1-NRG1Intrahepatic cholangiocarcinomaAfatinib 40 mg daily with dose reduction to 30 mg daily8 moJones et al., 201721Jones M.R. Lim H. Shen Y. et al.Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer.Ann Oncol. 2017; 28: 3092-3097Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar562FCD74-NRG1Lung IMAAfatinib 40 mg daily6.1 mo (26 weeks)Cheema et al., 201722Cheema P.K. Doherty M. Tsao M.S. A case of invasive mucinous pulmonary adenocarcinoma with a CD74-NRG1 fusion protein targeted with afatinib.J Thorac Oncol. 2017; 12: e200-e202Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar686MCD74-NRG1Lung IMAGSK2849330aIncludes one case of NRG1+ intrahepatic cholangiocarcinoma (case 4). (anti-HER3 mAb)19 mobInhibits NRG1 binding to HER3 and inhibits HER3 heterodimeriziation.Drilon et al., 201813Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar781MCD74-NRG1Lung IMAAfatinib 40 mg dailyStable disease for 6 wkDrilon et al., 201813Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar856FSDC4-NRG1Lung IMAAfatinib 40 mg dailyProgression diseaseDrilon et al., 201813Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar951MCD74-NRG1Lung IMAAfatinib 40 mg dailyProgressive diseaseDrilon et al., 201813Drilon A. Somwar R. Mangatt B.P. et al.Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers.Cancer Discov. 2018; 8: 686-695Crossref PubMed Scopus (107) Google Scholar1055FSLC3A2-NRG1Lung IMALumretuzumabcNo response to afatinib after disease progression on GSK2849330; lumretuzumab is an anti-HER3 mAb. + erlotinibStable disease for ∼ 3.8 moKim et al., 201823Kim H.S. Han J.Y. Shin D.H. et al.EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion.Lung Cancer. 2018; 124: 71-75Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar1142FSLC3A2-NRG1Lung IMALumretuzumab + erlotinibStable disease for ∼ 3.8 moKim et al., 201823Kim H.S. Han J.Y. Shin D.H. et al.EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion.Lung Cancer. 2018; 124: 71-75Abstract Full Text Full Text PDF PubMed Scopus (20) Google ScholarIMA, Invasive mucinous adenocarcinoma; M, Male; F, Female; LUAC, lung adenocarcinoma; mAb, monoclonal antibody.a Includes one case of NRG1+ intrahepatic cholangiocarcinoma (case 4).b Inhibits NRG1 binding to HER3 and inhibits HER3 heterodimeriziation.c No response to afatinib after disease progression on GSK2849330; lumretuzumab is an anti-HER3 mAb. Open table in a new tab IMA, Invasive mucinous adenocarcinoma; M, Male; F, Female; LUAC, lung adenocarcinoma; mAb, monoclonal antibody. In summary, it will be incumbent upon translational scientists and clinical investigators to turn NRG1+ fusions into another successfully actionable driver mutation in oncology. Research should investigate any role of fusion partners/specific NRG1 breakpoints in NRG1+ NSCLC that may determine differences in clinicopathologic presentation (ie predilection for CNS metastasis) and treatment response given the diversity of fusion partners identified in NRG1+ NSCLC. Given the rarity of NRG1+ fusions in solid malignancies not just NSCLC, a cost-effective screening strategy to allow a tumor-agnostic treatment strategy approach reminiscent of targeting NTRK+ fusions should be deployed.30Drilon A. Laetsch T.W. Kummar S. et al.Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018; 378: 731Crossref PubMed Scopus (1528) Google Scholar