


国际肿瘤学杂志››2025,Vol. 52››Issue (4): 237-241.doi:10.3760/cma.j.cn371439-20241115-00039
收稿日期:2024-11-15修回日期:2025-02-26出版日期:2025-04-08发布日期:2025-04-21通讯作者:常建华,Email:changjianhua@163.com基金资助:
Tang Lei, Cai Zongyou, Chang Jianhua(
)
Received:2024-11-15Revised:2025-02-26Online:2025-04-08Published:2025-04-21Supported by:
摘要:
RET原癌基因编码的RET蛋白是一种受体酪氨酸激酶,可作为非小细胞肺癌(NSCLC)潜在的治疗靶点。在NSCLC中,RET融合变异发生率为1%~2%,多见于年轻、不吸烟患者。传统化疗、免疫治疗和多靶点激酶抑制剂在RET融合NSCLC患者中的疗效有限,但选择性RET抑制剂,如塞普替尼和普拉替尼,显著改善了此类患者的预后。选择性RET抑制剂耐药后的治疗策略是未来的研究方向。
唐磊, 蔡宗佑, 常建华. RET原癌基因与非小细胞肺癌的研究现状[J]. 国际肿瘤学杂志, 2025, 52(4): 237-241.
Tang Lei, Cai Zongyou, Chang Jianhua. Research updates of RET proto-oncogene in non-small cell lung cancer[J]. Journal of International Oncology, 2025, 52(4): 237-241.
| [1] | Rodak O, Peris-Díaz MD, Olbromski M, et al. Current landscape of non-small cell lung cancer: epidemiology, histological classification, targeted therapies, and immunotherapy[J].Cancers (Basel),2021,13(18): 4705. DOI:10.3390/cancers13184705. |
| [2] | Chevallier M, Borgeaud M, Addeo A, et al. Oncogenic driver mutations in non-small cell lung cancer: past, present and future[J].World J Clin Oncol,2021,12(4): 217-237. DOI:10.5306/wjco.v12.i4.217. pmid:33959476 |
| [3] | O'Leary C, Xu W, Pavlakis N, et al. Rearranged during transfection fusions in non-small cell lung cancer[J].Cancers (Basel),2019,11(5): 620. DOI:10.3390/cancers11050620. |
| [4] | Chen MF, Repetto M, Wilhelm C, et al. RET inhibitors in RET fusion-positive lung cancers: past, present, and future[J].Drugs,2024,84(9): 1035-1053. DOI:10.1007/s40265-024-02040-5. pmid:38997570 |
| [5] | Riely GJ, Wood DE, Ettinger DS, et al. Non-Small Cell Lung Cancer, Version 4.2024, NCCN Clinical Practice Guidelines in Oncology[J].J Natl Compr Canc Netw,2024,22(4): 249-274. DOI:10.6004/jnccn.2204.0023. |
| [6] | Parimi V, Tolba K, Danziger N, et al. Genomic landscape of 891 RET fusions detected across diverse solid tumor types[J].NPJ Precis Oncol,2023,7(1): 10. DOI:10.1038/s41698-023-00347-2. |
| [7] | Lu C, Dong XR, Zhao J, et al. Association of genetic and immuno-characteristics with clinical outcomes in patients with RET-rearranged non-small cell lung cancer: a retrospective multicenter study[J].J Hematol Oncol,2020,13(1): 37. DOI:10.1186/s13045-020-00866-6. |
| [8] | Zhu YC, Wang WX, Zhang QX, et al. The KIF5B-RET fusion gene mutation as a novel mechanism of acquired EGFR tyrosine kinase inhibitor resistance in lung adenocarcinoma[J].Clin Lung Cancer,2019,20(1): e73-e76. DOI:10.1016/j.cllc.2018.09.011. |
| [9] | Hess LM, Han Y, Zhu YE, et al. Characteristics and outcomes of patients with RET-fusion positive non-small lung cancer in real-world practice in the United States[J].BMC Cancer,2021,21(1): 28. DOI:10.1186/s12885-020-07714-3. |
| [10] | Feng J, Li Y, Wei B, et al. Clinicopathologic characteristics and diagnostic methods of RET rearrangement in Chinese non-small cell lung cancer patients[J].Transl Lung Cancer Res,2022,11(4): 617-631. DOI:10.21037/tlcr-22-202. |
| [11] | Shen T, Pu X, Wang L, et al. Association between RET fusions and efficacy of pemetrexed-based chemotherapy for patients with advanced NSCLC in China: a multicenter retrospective study[J].Clin Lung Cancer,2020,21(5): e349-e354. DOI:10.1016/j.cllc.2020.02.006. |
| [12] | Dantoing E, Piton N, Salaün M, et al. Anti-PD1/PD-L1 immunotherapy for non-small cell lung cancer with actionable oncogenic driver mutations[J].Int J Mol Sci,2021,22(12): 6288. DOI:10.3390/ijms22126288. |
| [13] | Liang W, Guo M, Pan Z, et al. Association between certain non-small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death-ligand 1 inhibition[J].Cancer Sci,2019,110(6): 2014-2021. DOI:10.1111/cas.14032. |
| [14] | Guisier F, Dubos-Arvis C, Viñas F, et al. Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or Met mutations or RET translocation: GFPC 01-2018[J].J Thorac Oncol,2020,15(4): 628-636. DOI:10.1016/j.jtho.2019.12.129. |
| [15] | Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry[J].Ann Oncol,2019,30(8): 1321-1328. DOI:10.1093/annonc/mdz167. pmid:31125062 |
| [16] | Knetki-Wróblewska M, Wojas-Krawczyk K, Kowalski DM, et al. Non-small-cell lung cancer patients with coexistence of high PD-L1 expression and RET fusion-which path should we follow? Case reports and literature review[J].J Clin Med,2022,11(6): 1630. DOI:10.3390/jcm11061630. |
| [17] | Offin M, Guo R, Wu SL, et al. Immunophenotype and response to immunotherapy of RET-rearranged lung cancers[J].JCO Precis Oncol,2019, 3: PO. 18.00386. DOI:10.1200/PO.18.00386. |
| [18] | Aldea M, Marinello A, Duruisseaux M, et al. RET-MAP: an international multicenter study on clinicobiologic features and treatment response in patients with lung cancer harboring a RET fusion[J].J Thorac Oncol,2023,18(5): 576-586. DOI:10.1016/j.jtho.2022.12.018. |
| [19] | 谢红霞, 左金辉, 廖冬颖, 等. PD-L1抑制剂在非小细胞肺癌中的应用[J].国际肿瘤学杂志,2022,49(2): 111-115. DOI:10.3760/cma.j.cn371439-20210121-00018. |
| [20] | Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial[J].Lancet Oncol,2016,17(12): 1653-1660. DOI:10.1016/S1470-2045(16)30562-9. pmid:27825636 |
| [21] | Lee SH, Lee JK, Ahn MJ, et al. Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase Ⅱ clinical trial[J].Ann Oncol,2017,28(2): 292-297. DOI:10.1093/annonc/mdw559. pmid:27803005 |
| [22] | Hida T, Velcheti V, Reckamp KL, et al. A phase 2 study of lenvatinib in patients with RET fusion-positive lung adenocarcinoma[J].Lung Cancer,2019,138: 124-130. DOI:10.1016/j.lungcan.2019.09.011. pmid:31710864 |
| [23] | Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer[J].N Engl J Med,2020,383(9): 813-824. DOI:10.1056/NEJMoa2005653. |
| [24] | Subbiah V, Gainor JF, Oxnard GR, et al. Intracranial efficacy of selpercatinib in RET fusion-positive non-small cell lung cancers on the LIBRETTO-001 trial[J].Clin Cancer Res,2021,27(15): 4160-4167. DOI:10.1158/1078-0432.CCR-21-0800. pmid:34088726 |
| [25] | Minchom A, Tan AC, Massarelli E, et al. Patient-reported outcomes with selpercatinib among patients with RET fusion-positive non-small cell lung cancer in the phase Ⅰ/Ⅱ LIBRETTO-001 trial[J].Oncologist,2022,27(1): 22-29. DOI:10.1002/onco.13976. |
| [26] | Lu S, Cheng Y, Huang D, et al. Efficacy and safety of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer: a phase Ⅱ clinical trial (LIBRETTO-321)[J].Ther Adv Med Oncol,2022,14: 17588359221105020. DOI:10.1177/17588359221105020. |
| [27] | Cheng Y, Huang D, Zhou J, et al. Intracranial activity of selpercatinib in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer in the phase Ⅱ LIBRETTO-321 trial[J].JCO Precis Oncol,2023,7: e2200708. DOI:10.1200/PO.22.00708. |
| [28] | Zhou C, Solomon B, Loong HH, et al. First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion-positive NSCLC[J].N Engl J Med,2023,389(20): 1839-1850. DOI:10.1056/NEJMoa2309457. |
| [29] | Griesinger F, Curigliano G, Thomas M, et al. Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial[J].Ann Oncol,2022,33(11): 1168-1178. DOI:10.1016/j.annonc.2022.08.002. pmid:35973665 |
| [30] | Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study[J].Lancet Oncol,2021,22(7): 959-969. DOI:10.1016/S1470-2045(21)00247-3 pmid:34118197 |
| [31] | U.S. FOOD and Drug Administration.FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer[EB/OL]. (2022-09-21)[2025-01-19]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-non-small-cell-lung. |
| [32] | U.S. FOOD and Drug Administration.FDA approves pralsetinib for non-small cell lung cancer with RET gene fusions[EB/OL]. (2023-08-09)[2025-01-19]. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions. |
| [33] | 国家食品药品监督管理局.2022年10月09日药品批准证明文件待领取信息发布[EB/OL]. (2022-10-09)[2025-01-19]. https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20221009160008139.html. |
| [34] | 国家食品药品监督管理局.2023年06月26日药品批准证明文件送达信息发布[EB/OL]. (2023-06-26)[2025-01-19]. https://www.nmpa.gov.cn/zwfw/sdxx/sdxxyp/yppjfb/20230626133635185.html. |
| [35] | Solomon BJ, Tan L, Lin JJ, et al. RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies[J].J Thorac Oncol,2020,15(4): 541-549. DOI:10.1016/j.jtho.2020.01.006. |
| [36] | Zhou Y, Xiang S, Yang F, et al. Targeting gatekeeper mutations for kinase drug discovery[J].J Med Chem,2022,65(23): 15540-15558. DOI:10.1021/acs.jmedchem.2c01361. pmid:36395392 |
| [37] | Wirth LJ, Kohno T, Udagawa H, et al. Emergence and targeting of acquired and hereditary resistance to multikinase RET inhibition in patients with RET-altered cancer[J].JCO Precis Oncol,2019, 3: PO. 19.00189. DOI:10.1200/PO.19.00189. |
| [38] | Subbiah V, Shen T, Terzyan SS, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations[J].Ann Oncol,2021,32(2): 261-268. DOI:10.1016/j.annonc.2020.10.599. pmid:33161056 |
| [39] | 中国抗癌协会肿瘤精准治疗专业委员会, 中华医学会杂志社肺癌研究协作组, 中国临床肿瘤学会非小细胞肺癌专家委员会. 晚期RET融合阳性非小细胞肺癌诊疗中国专家共识(2023版)[J].中华肿瘤杂志,2023,45(12): 991-1002. DOI:10.3760/cma.j.cn112152-20230711-00290. |
| [40] | Lin JJ, Liu SV, McCoach CE, et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer[J].Ann Oncol,2020,31(12): 1725-1733. DOI:10.1016/j.annonc.2020.09.015. pmid:33007380 |
| [41] | Rosen EY, Won HH, Zheng Y, et al. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers[J].Nat Commun,2022,13(1): 1450. DOI:10.1038/s41467-022-28848-x. |
| [42] | Khatri U, Dayal N, Hu X, et al. Targeting RET solvent-front mutants with alkynyl nicotinamide-based inhibitors[J].Mol Cancer Ther,2023,22(6): 717-725. DOI:10.1158/1535-7163.MCT-22-0629. |
| [43] | Miyazaki I, Odintsov I, Ishida K, et al. Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations[J].Nat Cancer,2023,4(9): 1345-1361. DOI:10.1038/s43018-023-00630-y. |
| [44] | ClinicalTrials. gov.Phase Ⅰ/Ⅱ study of the selective RET inhibitor TAS0953/HM06 in patients with advanced solid tumors with RET gene abnormalities[EB/OL]. (2020-12-16)[2025-01-19]. https://clinicaltrials.gov/study/NCT04683250. |
| [45] | 中国临床肿瘤学会指南工作委员会.中国临床肿瘤学会(CSCO)非小细胞肺癌诊疗指南2024[M]. 北京: 人民卫生出版社,2024. |
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