Download PDF
CC BY 4.0 · Glob Med Genet 2024; 11(01): 086-099
DOI: 10.1055/s-0044-1781457
Review Article

Expert Consensus on the Diagnosis and Treatment of NRG1/2 Gene Fusion Solid Tumors

Chunwei Xu   *
1   Department of Scientific Research, Institute of Cancer and Basic Medicine, Chinese Academy of Sciences, Hangzhou Zhejiang, People's Republic of China
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Qian Wang   *
3   Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing Jiangsu, People's Republic of China
,
Dong Wang   *
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Wenxian Wang   *
4   Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
,
Wenfeng Fang   *
5   Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou Guangdong, People's Republic of China
,
Ziming Li
6   Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Aijun Liu
7   Senior Department of Pathology, the 7th Medical Center of PLA General Hospital, Beijing, People's Republic of China
,
Jinpu Yu
8   Department of Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
,
Wenzhao Zhong
9   Department of Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou Guangdong, People's Republic of China
,
Zhijie Wang
10   State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
,
Yongchang Zhang
11   Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha Hunan, People's Republic of China
,
Jingjing Liu
12   Department of Thoracic Cancer, Jilin Cancer Hospital, Jilin Changchun, People's Republic of China
,
Shirong Zhang
13   Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou Zhejiang, People's Republic of China
,
Xiuyu Cai
14   Department of VIP Inpatient, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People's Republic of China
,
Anwen Liu
15   Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi, People's Republic of China
,
Wen Li
16   Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou Zhejiang, People's Republic of China
,
Ping Zhan
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Hongbing Liu
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Tangfeng Lv
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Liyun Miao
17   Department of Respiratory Medicine, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Lingfeng Min
18   Department of Respiratory Medicine, Clinical Medical School of Yangzhou University, Subei People's Hospital of Jiangsu Province, Yangzhou Jiangsu, People's Republic of China
,
Yu Chen
19   Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou Fujian, People's Republic of China
,
Jingping Yuan
20   Department of Pathology, Renmin Hospital of Wuhan University, Wuhan Hubei, People's Republic of China
,
Feng Wang
21   Department of Internal Medicine, Cancer Center of PLA, Qinhuai Medical Area, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People's Republic of China
,
Zhansheng Jiang
22   Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
,
Gen Lin
19   Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou Fujian, People's Republic of China
,
Long Huang
15   Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi, People's Republic of China
,
Xingxiang Pu
23   Department of Medical Oncology, Lung Cancer and Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha Hunan, People's Republic of China
,
Rongbo Lin
19   Department of Medical Oncology, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou Fujian, People's Republic of China
,
Weifeng Liu
24   Department of Orthopaedic Oncology Surgery, Beijing Ji Shui Tan Hospital, Peking University, Beijing, People's Republic of China
,
Chuangzhou Rao
25   Department of Radiotherapy and Chemotherapy, Hwamei Hospital, University of Chinese Academy of Sciences, Ningbo Zhejiang, People's Republic of China
,
Dongqing Lv
26   Department of Pulmonary Medicine, Taizhou Hospital of Wenzhou Medical University, Taizhou Zhejiang, People's Republic of China
,
Zongyang Yu
27   Department of Respiratory Medicine, the 900th Hospital of the Joint Logistics Team (the Former Fuzhou General Hospital), Fujian Medical University, Fuzhou Fujian, People's Republic of China
,
Xiaoyan Li
28   Department of Oncology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China
,
Chuanhao Tang
29   Department of Medical Oncology, Peking University International Hospital, Beijing, People's Republic of China
,
Chengzhi Zhou
30   Department of State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University (The First Affiliated Hospital of Guangzhou Medical University), Guangzhou Guangdong, People's Republic of China
,
Junping Zhang
31   Department of Thoracic Oncology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan Shanxi, People's Republic of China
,
Junli Xue
32   Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China
,
Hui Guo
33   Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Shaanxi, People's Republic of China
,
Qian Chu
34   Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei, People's Republic of China
,
Rui Meng
35   Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei, People's Republic of China
,
Jingxun Wu
36   Department of Medical Oncology, the First Affiliated Hospital of Medicine, Xiamen University, Xiamen Fujian, People's Republic of China
,
Rui Zhang
37   Department of Medical Oncology, Cancer Hospital of China Medical University, Shenyang Liaoning, People's Republic of China
,
Jin Zhou
38   Department of Medical Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology, Chengdu Sichuan, People's Republic of China
,
Zhengfei Zhu
39   Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
,
Yongheng Li
40   Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
,
Hong Qiu
34   Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei, People's Republic of China
,
Fan Xia
39   Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
,
Yuanyuan Lu
41   Department of State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an Shaanxi, People's Republic of China
,
Xiaofeng Chen
42   Department of Oncology, Jiangsu Province Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing Jiangsu, People's Republic of China
,
Rui Ge
43   Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, People's Republic of China
,
Enyong Dai
44   Department of Oncology and Hematology, China-Japan Union Hospital of Jilin University, Changchun Jilin, People's Republic of China
,
Yu Han
45   Department of Gastrointestinal Oncology, Harbin Medical University Cancer Hospital, Harbin Heilongjiang, People's Republic of China
,
Weiwei Pan
46   Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing Zhejiang, People's Republic of China
,
Fei Pang
47   Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai, People's Republic of China
,
Qingqing He
47   Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai, People's Republic of China
,
Jintao Huang
47   Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai, People's Republic of China
,
Kai Wang
47   Department of Medical, Shanghai OrigiMed Co., Ltd., Shanghai, People's Republic of China
,
Fan Wu
48   Department of Medical, Stone Pharmaceuticals (Suzhou) Co., Ltd., Shanghai, People's Republic of China
,
Bingwei Xu
49   Department of Biotherapy, Cancer Institute, First Affiliated Hospital of China Medical University, Shenyang, People's Republic of China
,
Liping Wang
50   Department of Oncology, Baotou Cancer Hospital, Baotou Inner Mongolia, People's Republic of China
,
Youcai Zhu
51   Department of Thoracic Disease Diagnosis and Treatment Center, Zhejiang Rongjun Hospital, The Third Affiliated Hospital of Jiaxing University, Jiaxing Zhejiang, People's Republic of China
,
Li Lin
29   Department of Medical Oncology, Peking University International Hospital, Beijing, People's Republic of China
,
Yanru Xie
52   Department of Oncology, Lishui Municipal Central Hospital, Lishui Zhejiang, People's Republic of China
,
Xinqing Lin
30   Department of State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University (The First Affiliated Hospital of Guangzhou Medical University), Guangzhou Guangdong, People's Republic of China
,
Jing Cai
15   Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang Jiangxi, People's Republic of China
,
Ling Xu
53   Department of Interventional Pulmonary Diseases, Anhui Chest Hospital, Hefei Anhui, People's Republic of China
,
Jisheng Li
54   Department of Medical Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinnan Shangdong, People's Republic of China
,
Xiaodong Jiao
55   Department of Medical Oncology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai, People's Republic of China
,
Kainan Li
56   Department of Oncology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan Shandong, People's Republic of China
,
Jia Wei
57   Department of the Comprehensive Cancer Center, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Huijing Feng
31   Department of Thoracic Oncology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan Shanxi, People's Republic of China
,
Lin Wang
58   Department of Pathology, Shanxi Academy of Medical Sciences, Shanxi Bethune Hospital, Taiyuan Shanxi, People's Republic of China
,
Yingying Du
59   Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei Anhui, People's Republic of China
,
Wang Yao
60   Department of Interventional Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou Guangdong, People's Republic of China
,
Xuefei Shi
61   Department of Respiratory Medicine, Huzhou Hospital, Zhejiang University School of Medicine, Huzhou Zhejiang, People's Republic of China
,
Xiaomin Niu
6   Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People's Republic of China
,
Dongmei Yuan
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Yanwen Yao
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Jianhui Huang
52   Department of Oncology, Lishui Municipal Central Hospital, Lishui Zhejiang, People's Republic of China
,
Yue Feng
62   Department of Gynecologic Radiation Oncology, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
,
Yinbin Zhang
63   Department of Oncology, the Second Affiliated Hospital of Medical College, Xi′an Jiaotong University, Xi'an Shaanxi, People's Republic of China
,
Pingli Sun
64   Department of Pathology, The Second Hospital of Jilin University, Changchun Jilin, People's Republic of China
,
Hong Wang
65   Senior Department of Oncology, The 5th Medical Center of PLA General Hospital, Beijing, People's Republic of China
,
Mingxiang Ye
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Zhaofeng Wang
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Yue Hao
4   Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
,
Zhen Wang
66   Department of Radiation Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People's Republic of China
,
Bin Wan
67   Department of Respiratory Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing Jiangsu, People's Republic of China
,
Donglai Lv
68   Department of Clinical Oncology, The 901 Hospital of Joint Logistics Support Force of People Liberation Army, Hefei Anhui, People's Republic of China
,
Shengjie Yang
69   Department of Thoracic Surgery, Chuxiong Yi Autonomous Prefecture People's Hospital, Chuxiong, People's Republic of China
,
Jin Kang
9   Department of Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou Guangdong, People's Republic of China
,
Jiatao Zhang
9   Department of Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou Guangdong, People's Republic of China
,
Chao Zhang
9   Department of Guangdong Lung Cancer Institute, Guangdong Provincial Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangzhou Guangdong, People's Republic of China
,
Juanjuan Ou
70   Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China
,
Lin Shi
71   Department of Respiratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
,
Yina Wang
72   Department of Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou Zhejiang, People's Republic of China
,
Bihui Li
73   Department of Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin Guangxi, People's Republic of China
,
Zhang Zhang
74   Department of International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, Guangdong, People's Republic of China
,
Zhongwu Li
75   Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
,
Zhefeng Liu
65   Senior Department of Oncology, The 5th Medical Center of PLA General Hospital, Beijing, People's Republic of China
,
Nong Yang
11   Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha Hunan, People's Republic of China
,
Lin Wu
23   Department of Medical Oncology, Lung Cancer and Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha Hunan, People's Republic of China
,
Huijuan Wang
76   Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou Henan, People's Republic of China
,
Gu Jin
77   Department of Bone and Soft-tissue Surgery, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou Zhejiang, People's Republic of China
,
Guansong Wang
78   Institute of Respiratory Diseases, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China
,
Jiandong Wang
79   Department of Pathology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People's Republic of China
,
Meiyu Fang
3   Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing Jiangsu, People's Republic of China
,
Yong Fang
80   Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou Zhejiang, People's Republic of China
,
Yuan Li
81   Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, People's Republic of China
,
Xiaojia Wang
4   Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
,
Yiping Zhang
4   Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
,
Xixu Zhu
66   Department of Radiation Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, People's Republic of China
,
Yi Shen
82   Department of Thoracic Surgery, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Shenglin Ma
83   Department of Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou Cancer Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou Zhejiang, People's Republic of China
,
Biyun Wang
84   Department of Breast Cancer and Urological Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
,
Lu Si
85   Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Melanoma and Sarcoma, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
,
Yong Song
2   Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing Jiangsu, People's Republic of China
,
Yuanzhi Lu
86   Department of Clinical Pathology, the First Affiliated Hospital of Jinan University, Guangzhou Guangdong, People's Republic of China
,
Jing Chen
35   Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei, People's Republic of China
,
Zhengbo Song
4   Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, People's Republic of China
› Author Affiliations Funding This work was supported by the Natural Science Foundation of China (grant numbers 82002456), China Postdoctoral Science Foundation (grant numbers 2022M723207), the Medical Scientific Research Foundation of Zhejiang Province of China (grant numbers 2023KY666), Zhejiang Traditional Chinese Medicine Science Fund Project (grant numbers 2024ZL372), Qiantang Cross Fund Project (grant numbers 2023-16), National Natural Science Foundation of China of Zhejiang Cancer Hospital Cultivation Project (grant numbers PY2023006), the Medical Scientific Research Foundation of Zhejiang Province of China (grant numbers 2024KY812), and The Natural Science Foundation of Zhejiang Province (grant numbers Q24H160110).
› Further Information
Also available at
   Permissions and Reprints

Abstract

The fusion genes NRG1 and NRG2, members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1-positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2. Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Keywords

tyrosine receptor kinase - monoclonal antibodies - precision medicine - targeted therapy - solid tumor - fusion

Authors' Contributions

J.C. and Z.S. participated in the design of the expert consensus. C.X., Q.W., D.W., W.W., and W.F. conceived of the expert consensus and participated in its design and other authors coordination and helped to draft the expert consensus. All authors read and approved the final manuscript.


* These authors contributed equally.




Publication History

Article published online:
27 February 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411 (6835) 355-365
    CrossrefPubMedSearch in Google Scholar
  • 2 Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003; 284 (01) 14-30
    CrossrefPubMedSearch in Google Scholar
  • 3 Jonna S, Feldman RA, Swensen J. et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res 2019; 25 (16) 4966-4972
    CrossrefPubMedSearch in Google Scholar
  • 4 Kohsaka S, Hayashi T, Nagano M. et al. Identification of novel CD74-NRG2α fusion from comprehensive profiling of lung adenocarcinoma in Japanese never or light smokers. J Thorac Oncol 2020; 15 (06) 948-961
    CrossrefPubMedSearch in Google Scholar
  • 5 Ou SI, Xiu J, Nagasaka M. et al. Identification of novel CDH1-NRG2α and F11R-NRG2α fusions in NSCLC plus additional novel NRG2α fusions in other solid tumors by whole transcriptome sequencing. JTO Clin Res Rep 2020; 2 (02) 100132
    PubMedSearch in Google Scholar
  • 6 Odiete O, Hill MF, Sawyer DB. Neuregulin in cardiovascular development and disease. Circ Res 2012; 111 (10) 1376-1385
    CrossrefPubMedSearch in Google Scholar
  • 7 Wilson KJ, Mill CP, Cameron EM, Hobbs SS, Hammer RP, Riese II DJ. Inter-conversion of neuregulin2 full and partial agonists for ErbB4. Biochem Biophys Res Commun 2007; 364 (02) 351-357
    CrossrefPubMedSearch in Google Scholar
  • 8 Hayes NV, Gullick WJ. The neuregulin family of genes and their multiple splice variants in breast cancer. J Mammary Gland Biol Neoplasia 2008; 13 (02) 205-214
    CrossrefPubMedSearch in Google Scholar
  • 9 Holmes WE, Sliwkowski MX, Akita RW. et al. Identification of heregulin, a specific activator of p185erbB2. Science 1992; 256 (5060) 1205-1210
    CrossrefPubMedSearch in Google Scholar
  • 10 Wen D, Peles E, Cupples R. et al. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell 1992; 69 (03) 559-572
    CrossrefPubMedSearch in Google Scholar
  • 11 Marchionni MA, Goodearl AD, Chen MS. et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 1993; 362 (6418) 312-318
    CrossrefPubMedSearch in Google Scholar
  • 12 Falls DL, Rosen KM, Corfas G, Lane WS, Fischbach GD. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell 1993; 72 (05) 801-815
    CrossrefPubMedSearch in Google Scholar
  • 13 Tzahar E, Levkowitz G, Karunagaran D. et al. ErbB-3 and ErbB-4 function as the respective low and high affinity receptors of all Neu differentiation factor/heregulin isoforms. J Biol Chem 1994; 269 (40) 25226-25233
    CrossrefPubMedSearch in Google Scholar
  • 14 Hanker AB, Brown BP, Meiler J. et al. Co-occurring gain-of-function mutations in HER2 and HER3 modulate HER2/HER3 activation, oncogenesis, and HER2 inhibitor sensitivity. Cancer Cell 2021; 39 (08) 1099-1114.e8
    CrossrefPubMedSearch in Google Scholar
  • 15 Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 2000; 19 (13) 3159-3167
    CrossrefPubMedSearch in Google Scholar
  • 16 Busfield SJ, Michnick DA, Chickering TW. et al. Characterization of a neuregulin-related gene, Don-1, that is highly expressed in restricted regions of the cerebellum and hippocampus. Mol Cell Biol 1997; 17 (07) 4007-4014
    CrossrefPubMedSearch in Google Scholar
  • 17 Higashiyama S, Horikawa M, Yamada K. et al. A novel brain-derived member of the epidermal growth factor family that interacts with ErbB3 and ErbB4. J Biochem 1997; 122 (03) 675-680
    CrossrefPubMedSearch in Google Scholar
  • 18 Carraway III KL, Weber JL, Unger MJ. et al. Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 1997; 387 (6632) 512-516
    CrossrefPubMedSearch in Google Scholar
  • 19 Hobbs SS, Coffing SL, Le AT. et al. Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation. Oncogene 2002; 21 (55) 8442-8452
    CrossrefPubMedSearch in Google Scholar
  • 20 Breuleux M. Role of heregulin in human cancer. Cell Mol Life Sci 2007; 64 (18) 2358-2377
    CrossrefPubMedSearch in Google Scholar
  • 21 Forster JA, Paul AB, Harnden P, Knowles MA. Expression of NRG1 and its receptors in human bladder cancer. Br J Cancer 2011; 104 (07) 1135-1143
    CrossrefPubMedSearch in Google Scholar
  • 22 Meyer D, Birchmeier C. Multiple essential functions of neuregulin in development. Nature 1995; 378 (6555) 386-390
    CrossrefPubMedSearch in Google Scholar
  • 23 Schaefer G, Fitzpatrick VD, Sliwkowski MX. Gamma-heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 1997; 15 (12) 1385-1394
    CrossrefPubMedSearch in Google Scholar
  • 24 Fernandez-Cuesta L, Thomas RK. Molecular pathways: targeting NRG1 fusions in lung cancer. Clin Cancer Res 2015; 21 (09) 1989-1994
    CrossrefPubMedSearch in Google Scholar
  • 25 Werr L, Plenker D, Dammert MA. et al. CD74-NRG1 fusions are oncogenic in vivo and induce therapeutically tractable ERBB2:ERBB3 heterodimerization. Mol Cancer Ther 2022; 21 (05) 821-830
    CrossrefPubMedSearch in Google Scholar
  • 26 Fernandez-Cuesta L, Plenker D, Osada H. et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 2014; 4 (04) 415-422
    CrossrefPubMedSearch in Google Scholar
  • 27 Adélaïde J, Huang HE, Murati A. et al. A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene. Genes Chromosomes Cancer 2003; 37 (04) 333-345
    CrossrefPubMedSearch in Google Scholar
  • 28 Huang HE, Chin SF, Ginestier C. et al. A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene. Cancer Res 2004; 64 (19) 6840-6844
    CrossrefPubMedSearch in Google Scholar
  • 29 Duruisseaux M, McLeer-Florin A, Antoine M. et al. NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma. Cancer Med 2016; 5 (12) 3579-3585
    CrossrefPubMedSearch in Google Scholar
  • 30 Jung 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 (07) 1107-1111
    CrossrefPubMedSearch in Google Scholar
  • 31 Jones MR, Williamson LM, Topham JT. et al. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma. Clin Cancer Res 2019; 25 (15) 4674-4681
    CrossrefPubMedSearch in Google Scholar
  • 32 Heining C, Horak P, Uhrig S. et al. NRG1 fusions in KRAS wild-type pancreatic cancer. Cancer Discov 2018; 8 (09) 1087-1095
    CrossrefPubMedSearch in Google Scholar
  • 33 Jones JT, Akita RW, Sliwkowski MX. Binding specificities and affinities of EGF domains for ErbB receptors. FEBS Lett 1999; 447 (2-3): 227-231
    CrossrefPubMedSearch in Google Scholar
  • 34 Cha YJ, Lee C, Joo B, Kim KA, Lee CK, Shim HS. Clinicopathological characteristics of NRG1 fusion-positive solid tumors in Korean patients. Cancer Res Treat 2023; 55 (04) 1087-1095
    CrossrefPubMedSearch in Google Scholar
  • 35 Yuan HCS, Wang L, Dong X, Wang A, Wang K. The landscape of NRG1 fusions based on NGS in Chinese solid tumor patients. ASCO 2022; x: e15073
    Search in Google Scholar
  • 36 Nagasaka M, Ou SI. Neuregulin 1 fusion-positive NSCLC. J Thorac Oncol 2019; 14 (08) 1354-1359
    CrossrefPubMedSearch in Google Scholar
  • 37 Drilon A, Duruisseaux M, Han JY. et al. Clinicopathologic features and response to therapy of NRG1 fusion-driven lung cancers: the eNRGy1 Global Multicenter Registry. J Clin Oncol 2021; 39 (25) 2791-2802
    CrossrefPubMedSearch in Google Scholar
  • 38 Nagasaka M, Ou SI. NRG1 and NRG2 fusion positive solid tumor malignancies: a paradigm of ligand-fusion oncogenesis. Trends Cancer 2022; 8 (03) 242-258
    CrossrefPubMedSearch in Google Scholar
  • 39 Trombetta D, Graziano P, Scarpa A. et al. Frequent NRG1 fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by phospho-ErbB3 expression. Oncotarget 2018; 9 (11) 9661-9671
    CrossrefPubMedSearch in Google Scholar
  • 40 Jones MR, Lim H, Shen Y. et al. Successful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer. Ann Oncol 2017; 28 (12) 3092-3097
    CrossrefPubMedSearch in Google Scholar
  • 41 Howarth KD, Mirza T, Cooke SL. et al. NRG1 fusions in breast cancer. Breast Cancer Res 2021; 23 (01) 3
    CrossrefPubMedSearch in Google Scholar
  • 42 Mercer TR, Gerhardt DJ, Dinger ME. et al. Targeted RNA sequencing reveals the deep complexity of the human transcriptome. Nat Biotechnol 2011; 30 (01) 99-104
    CrossrefPubMedSearch in Google Scholar
  • 43 Song Z, Xu C, He Y. et al. Simultaneous detection of gene fusions and base mutations in cancer tissue biopsies by sequencing dual nucleic acid templates in unified reaction. Clin Chem 2020; 66 (01) 178-187
    CrossrefPubMedSearch in Google Scholar
  • 44 Zheng Z, Liebers M, Zhelyazkova B. et al. Anchored multiplex PCR for targeted next-generation sequencing. Nat Med 2014; 20 (12) 1479-1484
    CrossrefPubMedSearch in Google Scholar
  • 45 Lanic MD, Le Loarer F, Rainville V. et al. Detection of sarcoma fusions by a next-generation sequencing based-ligation-dependent multiplex RT-PCR assay. Mod Pathol 2022; 35 (05) 649-663
    CrossrefPubMedSearch in Google Scholar
  • 46 Cadranel J, Liu SV, Duruisseaux M. et al. Therapeutic potential of afatinib in NRG1 fusion-driven solid tumors: a case series. Oncologist 2021; 26 (01) 7-16
    CrossrefPubMedSearch in Google Scholar
  • 47 Estrada-Bernal A, Le AT, Doak AE. et al. Tarloxotinib is a hypoxia-activated Pan-HER kinase inhibitor active against a broad range of HER-family oncogenes. Clin Cancer Res 2021; 27 (05) 1463-1475
    CrossrefPubMedSearch in Google Scholar
  • 48 Liu SV. NRG1 fusions: biology to therapy. Lung Cancer 2021; 158: 25-28
    CrossrefPubMedSearch in Google Scholar
  • 49 Odintsov I, Lui AJW, Sisso WJ. et al. The anti-HER3 mAb seribantumab effectively inhibits growth of patient-derived and isogenic cell line and xenograft models with oncogenic NRG1 fusions. Clin Cancer Res 2021; 27 (11) 3154-3166
    CrossrefPubMedSearch in Google Scholar
  • 50 Thavaneswaran S, Chan WY, Asghari R. et al. Clinical response to seribantumab, an anti-human epidermal growth factor receptor-3 immunoglobulin 2 monoclonal antibody, in a patient with metastatic pancreatic ductal adenocarcinoma harboring an NRG1 fusion. JCO Precis Oncol 2022; 6: e2200263
    CrossrefPubMedSearch in Google Scholar
  • 51 Meneses-Lorente G, Friess T, Kolm I. et al. Preclinical pharmacokinetics, pharmacodynamics, and efficacy of RG7116: a novel humanized, glycoengineered anti-HER3 antibody. Cancer Chemother Pharmacol 2015; 75 (04) 837-850
    CrossrefPubMedSearch in Google Scholar
  • 52 Shin DH, Jo JY, Han JY. Dual targeting of ERBB2/ERBB3 for the treatment of SLC3A2-NRG1-mediated lung cancer. Mol Cancer Ther 2018; 17 (09) 2024-2033
    CrossrefPubMedSearch in Google Scholar
  • 53 Geuijen CAW, De Nardis C, Maussang D. et al. Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade. Cancer Cell 2021; 39 (08) 1163-1164
    CrossrefPubMedSearch in Google Scholar
  • 54 Fontana E, Torga G, Fostea R. et al. Sustained tumor regression with zenocutuzumab, a bispecific antibody targeting human epidermal growth factor receptor 2/human epidermal growth factor receptor 3 signaling, in NRG1 fusion-positive, estrogen receptor-positive breast cancer after progression on a cyclin-dependent kinase 4/6 inhibitor. JCO Precis Oncol 2022; 6: e2100446
    CrossrefPubMedSearch in Google Scholar
  • 55 Schram AM, Odintsov I, Espinosa-Cotton M. et al. Zenocutuzumab, a HER2xHER3 bispecific antibody, is effective therapy for tumors driven by NRG1 gene rearrangements. Cancer Discov 2022; 12 (05) 1233-1247
    CrossrefPubMedSearch in Google Scholar
  • 56 Leung WY, Roxanis I, Sheldon H. et al. Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer. Oncotarget 2015; 6 (08) 5678-5694
    CrossrefPubMedSearch in Google Scholar
  • 57 Miyake TM, Pradeep S, Bayraktar E. et al. NRG1/ERBB3 pathway activation induces acquired resistance to XPO1 inhibitors. Mol Cancer Ther 2020; 19 (08) 1727-1735
    CrossrefPubMedSearch in Google Scholar
  • 58 Taniguchi H, Akagi K, Dotsu Y. et al. Pan-HER inhibitors overcome lorlatinib resistance caused by NRG1/HER3 activation in ALK-rearranged lung cancer. Cancer Sci 2023; 114 (01) 164-173
    CrossrefPubMedSearch in Google Scholar