Nrg1(Neuregulin-1)是一种编码神经调节蛋白1的基因,它通过与其受体家族ErbB(包括ErbB2和ErbB3)结合来激活下游信号通路,包括PI3K-AKT和MAPK细胞级联。Nrg1及其受体的表达和功能与多种生物学过程密切相关,包括细胞增殖、分化、存活、迁移和黏附。Nrg1的表达和功能受多种因素的调节,包括转录因子、表观遗传修饰和翻译后修饰。Nrg1的异常表达和功能与多种疾病的发生和发展有关,包括癌症、神经退行性疾病和精神疾病[1,2,3]。
在癌症中,Nrg1的基因融合是一种罕见的遗传变异,导致Nrg1的异常激活和下游信号通路的失调,从而促进肿瘤细胞的生长和扩散。Nrg1基因融合主要发生在非小细胞肺癌(NSCLC)、胰腺导管腺癌(PDAC)和其他实体瘤中,其发生率为不到1%。最常见的Nrg1基因融合是CD74-NRG1,它在侵袭性黏液腺癌(IMA)中最为常见。Nrg1基因融合可以激活ErbB信号通路,从而促进肿瘤细胞的生长和扩散。此外,Nrg1基因融合还可以导致肿瘤细胞对某些药物的抗性,从而降低治疗效果[4,5,6,7,8,9,10]。
为了治疗Nrg1基因融合相关的癌症,研究人员正在开发靶向ErbB信号通路的治疗方法。例如,afatinib是一种泛ErbB酪氨酸激酶抑制剂,可以抑制ErbB信号通路的活性,从而抑制肿瘤细胞的生长和扩散。此外,Zenocutuzumab是一种新型的双特异性IgG1抗体,可以同时靶向HER2和HER3蛋白,并通过“Dock & Block®”机制抑制Nrg1的结合。这些治疗方法在临床试验中显示出一定的疗效,为Nrg1基因融合相关的癌症患者提供了新的治疗选择[4,5,6,7,8,9,10]。
总之,Nrg1基因融合是一种罕见的遗传变异,与多种实体瘤的发生和发展有关。靶向ErbB信号通路的治疗方法为Nrg1基因融合相关的癌症患者提供了新的治疗选择。未来需要进一步研究Nrg1基因融合的生物学机制和治疗策略,以提高Nrg1基因融合相关癌症的治疗效果。
参考文献:
1. Laskin, J, Liu, S V, Tolba, K, Solca, F, Duruisseaux, M. 2020. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. In Annals of oncology : official journal of the European Society for Medical Oncology, 31, 1693-1703. doi:10.1016/j.annonc.2020.08.2335. https://pubmed.ncbi.nlm.nih.gov/32916265/
2. Zhang, Congwang, Mei, Wuxuan, Zeng, Changchun. 2022. Oncogenic Neuregulin 1 gene (NRG1) fusions in cancer: A potential new therapeutic opportunities. In Biochimica et biophysica acta. Reviews on cancer, 1877, 188707. doi:10.1016/j.bbcan.2022.188707. https://pubmed.ncbi.nlm.nih.gov/35247506/
3. Kim, Dong-Wan, Schram, Alison M, Hollebecque, Antoine, Ford, Jim, Goto, Koichi. 2024. The phase I/II eNRGy trial: Zenocutuzumab in patients with cancers harboring NRG1 gene fusions. In Future oncology (London, England), 20, 1057-1067. doi:10.2217/fon-2023-0824. https://pubmed.ncbi.nlm.nih.gov/38348690/
4. Rosas, Daniel, Raez, Luis E, Russo, Alessandro, Rolfo, Christian. 2021. Neuregulin 1 Gene (NRG1). A Potentially New Targetable Alteration for the Treatment of Lung Cancer. In Cancers, 13, . doi:10.3390/cancers13205038. https://pubmed.ncbi.nlm.nih.gov/34680187/
5. Kucharczyk, Tomasz, Nicoś, Marcin, Kucharczyk, Marek, Kalinka, Ewa. 2024. NRG1 Gene Fusions-What Promise Remains Behind These Rare Genetic Alterations? A Comprehensive Review of Biology, Diagnostic Approaches, and Clinical Implications. In Cancers, 16, . doi:10.3390/cancers16152766. https://pubmed.ncbi.nlm.nih.gov/39123493/
6. Saito, Motonobu, Shiraishi, Kouya, Kunitoh, Hideo, Yokota, Jun, Kohno, Takashi. 2016. Gene aberrations for precision medicine against lung adenocarcinoma. In Cancer science, 107, 713-20. doi:10.1111/cas.12941. https://pubmed.ncbi.nlm.nih.gov/27027665/
7. Grego-Bessa, Joaquim, Gómez-Apiñaniz, Paula, Prados, Belén, MacGrogan, Donal, de la Pompa, José Luis. 2023. Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development. In Circulation research, 133, 927-943. doi:10.1161/CIRCRESAHA.123.323321. https://pubmed.ncbi.nlm.nih.gov/37846569/
8. He, Xiao-Yan, Huang, Zhuo-Hui, Wang, Fei, Jia, Fu-Jun, Hou, Cai-Lan. 2023. Gene Polymorphisms and Expression of NRG1, DAOA, and DISC1 Genes in a Chinese Han Population with an Ultra-High Risk for Psychosis. In Neuropsychiatric disease and treatment, 19, 2521-2533. doi:10.2147/NDT.S434856. https://pubmed.ncbi.nlm.nih.gov/38029052/
9. Qian, Yunzhen, Gong, Yitao, Fan, Zhiyao, Yu, Xianjun, Liu, Chen. 2020. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. In Journal of hematology & oncology, 13, 130. doi:10.1186/s13045-020-00958-3. https://pubmed.ncbi.nlm.nih.gov/33008426/
10. Jung, Yeonjoo, Yong, Seunghui, Kim, Pora, Kim, Jhingook, Kim, Jaesang. . VAMP2-NRG1 Fusion Gene is a Novel Oncogenic Driver of Non-Small-Cell Lung Adenocarcinoma. In Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 10, 1107-11. doi:10.1097/JTO.0000000000000544. https://pubmed.ncbi.nlm.nih.gov/26134228/