Patients with neuregulin 1 (NRG1) rearranged cancer are suitable for the theranostic approach and targeted therapy
Authors:
O. Ondič 1,2; N. Ptáková 1,3; V. Janovský 4; J. Vančurová 4; M. Hósová 5; M. Michal 1; M. Pešek 6
Authors‘ workplace:
Bioptická laboratoř s. r. o., Plzeň
1; Šiklův ústav patologie, LF UK a FN Plzeň
2; 2. LF UK, Praha
3; Onkologické oddělení, Nemocnice České Budějovice
4; Oddělení patologicko-anatomické, FN Bulovka, Praha
5; Klinika pneumologie a ftizeologie LF UK a FN Plzeň
6
Published in:
Klin Onkol 2022; 35(4): 271-275
Category:
Review
doi:
https://doi.org/10.48095/ccko2022271
Overview
Introduction: Neuregulin 1 (NRG1) gene fusion was detected in a wide range of carcinomas. It is most frequently present in lung adenocarcinomas, especially in KRAS and BRAF wild-type cases. Purpose: We present a newly described diverse group of NRG1 rearranged carcinomas. The paper explains basic molecular principles associated with this oncogenic driver. It consists of ERBB3 (HER3) and ERBB2 (HER2) receptor activation with downstream activation of PIK and MAPK canonical pathways. The experience with new therapeutic modalities is summarized. Conclusions: So far, the global results of cytotoxic, immune and targeted therapies were disappointing. Further research (including two studies in Europe) is underway, developing new therapeutic strategies and examining this cancer biology. In the meantime, it is possible to diagnose NRG1 rearranged carcinomas in the Czech Republic since mRNA next generation sequencing (NGS) analysis is readily available.
Keywords:
NRG 1 protein – neuregulin 1 – molecular targeted therapies – ERBB 2 protein – ERBB 3 protein – solid tumors
Sources
1. Schram AM, Chang MT, Jonsson P et al. Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance. Nat Rev Clin Oncol 2017; 14 (12): 735–748. doi: 10.1038/nrclinonc.2017.127.
2. Rossi G, Jocolle G, Conti A et al. Detection of ROS1 rearrangement in non-small cell lung cancer: current and future perspectives. Lung Cancer 2017; 8: 45–55. doi: 10.2147/LCTT.S120172.
3. Bronte G, Ulivi P, Verlicchi A et al. Targeting RET-rearranged non-small cell lung cancer: future prospects. Lung Cancer 2019; 10: 27–36. doi: 10.2147/LCTT.S192830.
4. Subbiah V, Velcheti V, Tuch BB et al. Selective RET kinase inhibition for patients with RET-altered cancers. Ann Oncol 2018; 29 (8): 1869–1876. doi: 10.1093/annonc/mdy137.
5. Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open 2016; 1 (2): e000023. doi: 10.1136/esmoopen-2015-000023.
6. Hsiao SJ, Zehir A, Sireci AN et al. Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy. J Mol Diagn 2019; 21 (4): 553–571. doi: 10.1016/j.jmoldx.2019.03.008.
7. Marcus L, Donoghue M, Aungst S et al. FDA approval summary: entrectinib for the treatment of NTRK gene fusion solid tumors. Clin Cancer Res 2021; 27 (4): 928–932. doi: 10.1158/1078-0432.CCR-20-2771.
8. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15 (12): 731–747. doi: 10.1038/s41571-018-0113-0.
9. Hickman JA, Tannock IF, Meheus L et al. The European Union and personalised cancer medicine. Eur J Cancer 2021; 150: 95–98. doi: 10.1016/j.ejca.2021.03.013.
10. Svaton M, Pešek M. Successful therapy of Czech patients with ROS1 translocation by crizotinib. Klin Onkol 2016; 29 (1): 63–65. doi: 10.14735/amko201663.
11. Bratova M, Karlinova B, Skrickova J et al. Non-small cell lung cancer as a chronic disease – a prospective study from the Czech TULUNG registry. In Vivo 2020; 34 (1): 369–379. doi: 10.21873/invivo.11783.
12. Brat K, Bratova M, Skrickova J et al. Real-life effectiveness of first-line anticancer treatments in stage IIIB/IV NSCLC patients: data from the Czech TULUNG registry. Thorac Cancer 2020; 11 (11): 3346–3356. doi: 10.1111/1759-7714.13679.
13. Meyer D, Yamaai T, Garratt A et al. Isoform-specific expression and function of neuregulin. Development 1997; 124 (18): 3575–3586. doi: 10.1242/dev.124.18.3575.
14. Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res 2003; 284 (1): 14–30. doi: 10.1016/s0014-4827 (02) 00102-7.
15. Hynes NE, MacDonald G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol 2009; 21 (2): 177–184. doi: 10.1016/j.ceb.2008.12.010.
16. Hobbs SS, Coffing SL, Le AT et al. Neuregulin isoforms exhibit distinct patterns of ErbB family receptor activation. Oncogene 2002; 21 (55): 8442–8452. doi: 10.1038/sj.onc.1205960.
17. Arkhipov A, Shan Y, Das R et al. Architecture and membrane interactions of the EGF receptor. Cell 2013; 152 (3): 557–569. doi: 10.1016/j.cell.2012.12.030.
18. Tsai CJ, Nussinov R. Emerging allosteric mechanism of EGFR activation in physiological and pathological contexts. Biophys J 2019; 117 (1): 5–13. doi: 10.1016/j.bpj.2019.05.021.
19. Jonna S, Feldman RA, Swensen J et al. Detection of NRG1 gene fusions in solid tumors. Clin Cancer Res 2019; 25 (16): 4966–4972. doi: 10.1158/1078-0432.CCR-19-0160.
20. Drilon A, Somwar R, Mangatt BP et al. Response to ERBB3-directed targeted therapy in NRG1-rearranged cancers. Cancer Discov 2018; 8 (6): 686–695. doi: 10.1158/2159-8290.CD-17-1004.
21. Ptáková N, Martínek P, Holubec L et al. Identification of tumors with NRG1 rearrangement, including a novel putative pathogenic UNC5D-NRG1 gene fusion in prostate cancer by data-drilling a de-identified tumor database. Genes Chromosomes Cancer 2021; 60 (7): 474–481. doi: 10.1002/gcc.22942.
22. Nakaoku T, Tsuta K, Ichikawa H et al. Druggable oncogene fusions in invasive mucinous lung adenocarcinoma. Clin Cancer Res 2014; 20 (12): 3087–3093. doi: 10.1158/1078-0432.CCR-14-0107.
23. Shim HS, Kenudson M, Zheng Z et al. Unique genetic and survival characteristics of ivasive mucinous adenocarcinoma of the lung. J Thorac Oncol 2015; 10 (8): 1156–1162. doi: 10.1097/JTO.0000000000000579.
24. Chang JC, Offin M, Falcon C et al. Comprehensive molecular and clinicopathologic analysis of 200 pulmonary invasive mucinous adenocarcinomas identifies distinct characteristics of molecular subtypes. Clin Cancer Res 2021; 27 (14): 4066–4076. doi: 10.1158/1078-0432.CCR-21-0423.
25. Laskin J, Liu SV, Tolba K et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol 2020; 31 (12): 1693–1703. doi: 10.1016/j.annonc.2020.08.2335.
26. Cadranel J, Liu SV, Duruisseaux M et al. Therapeutic potential of Afatinib in NRG1 fusion-driven solid tumors: a case series. Oncologist 2020; 26 (1): 7–16. doi: 10.1634/theoncologist.2020-0379.
27. 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. doi: 10.1200/JCO.20.03307.
28. Gaborit N, Lindzen M, Yarden Y. Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. Hum Vaccin Immunother 2016; 12 (3): 576–592. doi: 10.1080/21645515.2015.1102809.
29. Mishra R, Patel H, Alanazi S et al. HER3 signaling and targeted therapy in cancer. Oncol Rev 2018; 12 (1): 355. doi: 10.4081/oncol.2018.355.
30. Schram AM, O’Reilly EM, Somwar R et al. Clinical proof of concept for MCLA-128, a bispecific HER2/3 antibody therapy, in NRG1 fusion-positive cancers. Mol Cancer Ther 2019; 18 (Suppl 12): PR02. doi: 10.1158/1535-7163.TARG-19-PR02.
31. Tirunagaru VG, Estrada-Bernal A, Yu H et al. Tarloxotinib exhibits potent activity in NRG1 fusion and rearranged cancers. Cancer Res 2019; 79 (Suppl 13): 2202a.
32. Study of seribantumab in adult patients with NRG1 gene fusion positive advanced solid tumors. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT04383210?term=NCT04383210&draw=2&rank=1.
33. A study of zenocutuzumab (MCLA-128) in patients with solid tumors harboring an NRG1 fusion. [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT02912949?term=NCT02912949&draw=2&rank=1.
34. Study of tarloxotinib in Pts with NSCLC (EGFR exon 20 insertion, HER2-activating mutations) & other solid tumors with NRG1/ERBB gene fusions (RAIN). [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT03805841?term=NCT+03805841&draw=2&rank=131.
35. Afatinib in advanced NRG1-rearranged malignancies: the NCT/DKTK PMO-1604 phase-II trial. [online]. Availabe from: https: //clinicaltrials.gov/ct2/show/record/NCT04410653?view=record.
36. 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. [online]. Available from: https: //clinicaltrials.gov/ct2/show/record/NCT04814056.
37. Dermawan JK, Zou Y, Antonescu CR. Neuregulin 1 (NRG1) fusion-positive high-grade spindle cell sarcoma: a distinct group of soft tissue tumors with metastatic potential. Genes Chromosomes Cancer 2022; 61 (3): 123–130. doi: 10.1002/gcc.23008.
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