EML4-ALK融合基因在非小细胞肺癌中的研究进展^*

Research progress on the EML4-ALK fusion gene in non-small cell lung cancer: molecular mechanisms and targeted therapies

摘要

肺癌是全球发病率及病死率较高的恶性肿瘤, 85%的肺癌属于非小细胞肺癌 (NSCLC)。随着分子生物学技术和靶向治疗药物的发展, NSCLC迈进了精准治疗时代。棘皮动物微管相关蛋白样4 (EML4)-间变性淋巴瘤激酶 (ALK) 融合基因是NSCLC个体化治疗的靶点之一, ALK抑制剂对其具有显著的治疗效果, 然而, 克服药物的耐药性一直是一个不容忽视的挑战, 寻找新的治疗靶点以及联合用药对于后续治疗方案的调整和整体预后评估具有重要意义。针对EML4-ALK基因融合患者的治疗, 在应用靶向药物的同时, 还应该持续监测肿瘤的发展进程, 根据病情及时调整治疗方案, 使得患者能够长期获益。本文围绕EML4-ALK融合基因详细论述其在临床病理特征、靶向药物研究、耐药机理及潜在新靶点等方面的研究新进展。

Abstract

Lung cancer is a malignant neoplasm characterized by a high incidence and fatality rate globally. Non-small cell lung cancer (NSCLC) constitutes 85% of lung cancer cases. The advancement of molecular biotechnology and tailored therapeutics has ushered NSCLC treatment into the era of precision medicine. The echinoderm microtubule associated protein like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene is a target for personalized therapy in NSCLC. ALK inhibitors exhibit substantial therapeutic efficacy. Nonetheless, surmounting drug resistance has consistently posed a significant barrier that warrants attention. Identifying novel therapeutic targets and employing combination medication therapies are crucial for refining subsequent treatment strategies and assessing overall prognosis. In the management of patients with EML4-ALK gene fusion, it is imperative to regularly monitor tumor progression while administering targeted therapies, and to timely modify the therapy regimen based on the patient's state to ensure long-term benefits. This article elaborates on recent advancements in research concerning the EML4-ALK fusion gene, focusing on its clinical pathological attributes targeted pharmacological investigations, mechanisms of treatment resistance, and prospective novel targets.

关键词

非小细胞肺癌 / EML4-ALK融合基因 / 临床病理特征 / 耐药机制 / 治疗靶点

Key words

Non-small cell lung cancer / EML4-ALK fusion gene / Clinicopathological characteristics / Drug resistance mechanism / Therapeutic targets

参考文献

[1] Bozorgmehr F, Müller A, Rawluk J, et al. Immune checkpoint inhibitors in non—small cell lung cancer—when should we dare to stop treatment? [J]. Lung Cancer, 2023, 184: 107340.

[2] Li X, Wang Z, Chen C, et al. A small—molecule degrader selectively inhibits the growth of ALK—rearranged lung cancer with ceritinib resistance [J]. iScience, 2024, 27(2): 109015.

[3] Xu J, Tian L, Qi W, et al. Advancements in NSCLC: from pathophysiological insights to targeted treatments [J]. Am J Clin Oncol, 2024, 47(6): 291-303.

[4] Chuang T P, Lai W Y, Gabre J L, et al. ALK fusion NSCLC oncogenes promote survival and inhibit NK cell responses via SERPINB4 expression [J]. Proc Natl Acad Sci U S A, 2023, 120(8): e2216479120.

[5] Xiang Y, Zhang S, Fang X, et al. Therapeutic advances of rare ALK fusions in non—small cell lung cancer [J]. Curr Oncol, 2022, 29(10): 7816-7831.

[6] Cheon S Y, Kwon S. Molecular anatomy of the EML4—ALK fusion protein for the development of novel anticancer drugs [J]. Int J Mol Sci, 2023, 24(6): 5821.

[7] Soda M, Choi Y L, Enomoto M, et al. Identification of the transforming EML4—ALK fusion gene in non—small—cell lung cancer [J]. Nature, 2007, 448(7153): 561-566.

[8] Lei Y, Lei Y, Shi X, et al. EML4—ALK fusion gene in non—small cell lung cancer [J]. Oncol Lett, 2022, 24(2): 277.

[9] Elshatlawy M, Sampson J, Clarke K, et al. EML4—ALK biology and drug resistance in non—small cell lung cancer: a new phase of discoveries [J]. Mol Oncol, 2023, 17(6): 950-963.

[10] Parikh K, Dimou A, Leventakos K, et al. Impact of EML4—ALK variants and co—occurring TP53 mutations on duration of first—line ALK tyrosine kinase inhibitor treatment and overall survival in ALK fusion—positive NSCLC: real—world outcomes from the guardant INFORM database [J]. J Thorac Oncol, 2024, 19(11): 1539-1549.

[11] Fu Y, Liu Q, Wang X, et al. Clinical difference on the variants and co—mutation in a Chinese cohort with ALK—positive advanced non—small cell lung cancer [J]. Clin Transl Oncol, 2024, 26(10): 2513-2521.

[12] Li L, Li W, Wu C, et al. Real—world data on ALK rearrangement test in Chinese advanced non—small cell lung cancer (RATICAL): a nationwide multicenter retrospective study [J]. Cancer Commun (Lond), 2024, 44(9): 992-1004.

[13] Maione P, Palma V, Pucillo G, et al. Targeting ALK receptors in non—small cell lung cancer: what is the road ahead? [J]. Expert Opin Ther Targets, 2024, 28(8): 659-668.

[14] Liu Q, Huang Q, Yu Z, et al. Clinical characteristics of non—small cell lung cancer patients with EGFR mutations and ALK&ROS1 fusions [J]. Clin Respir J, 2022, 16(3): 216-225.

[15] Shi J, Gu W, Zhao Y, et al. Clinicopathological and prognostic significance of EML4—ALK rearrangement in patients with surgically resected lung adenocarcinoma: a propensity score matching study [J]. Cancer Manag Res, 2020, 12: 589-598.

[16] Cai Y, Chen T, Zhang S, et al. Correlation exploration among CT imaging, pathology and genotype of pulmonary ground—glass opacity [J]. J Cell Mol Med, 2023, 27(14): 2021-2031.

[17] Chen M F, Chaft J E. Early—stage anaplastic lymphoma kinase (ALK)—positive lung cancer: a narrative review [J]. Transl Lung Cancer Res, 2023, 12(2): 337-345.

[18] Tan A C, Tan D. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations [J]. J Clin Oncol, 2022, 40(6): 611-625.

[19] Schneider J L, Lin J J, Shaw A T. ALK—positive lung cancer: a moving target [J]. Nat Cancer, 2023, 4(3): 330-343.

[20] Yang C, Zeng R, Zha Y, et al. Case report: clinical complete response in advanced ALK—positive lung squamous cell carcinoma: a case study of successful anti—PD—1 immunotherapy post ALK—TKIs failure [J]. Front Immunol, 2024, 15: 1360671.

[21] Solomon B J, Bauer T M, Mok T, et al. Efficacy and safety of first—line lorlatinib versus crizotinib in patients with advanced, ALK—positive non—small—cell lung cancer: updated analysis of data from the phase 3, randomised, open—label CROWN study [J]. Lancet Respir Med, 2023, 11(4): 354-366.

[22] Li M S, Ou S I. Iruplinalkib (WX—0593), the seventh ALK tyrosine kinase inhibitor approved in the People's Republic of China with more to come [J]. J Thorac Oncol, 2024, 19(6): 855-857.

[23] Balasundaram A, Doss G. A computational examination of the therapeutic advantages of fourth—generation ALK inhibitors TPX—0131 and repotrectinib over third—generation lorlatinib for NSCLC with ALK F1174C/L/V mutations [J]. Front Mol Biosci, 2023, 10: 1306046.

[24] Lu Y, Fan Z, Zhu S J, et al. A new ALK inhibitor overcomes resistance to first— and second—generation inhibitors in NSCLC [J]. EMBO Mol Med, 2022, 14(1): e14296.

[25] Cheng X, Liu J, Hu Q, et al. A novel secondary ALK gene mutation which resistant to second—generation TKIs: a case report and literature review [J]. Front Oncol, 2024, 14: 1430350.

[26] Jang C, Sabari J. Combinatorial therapy is a safe and durable treatment option in ALK—rearranged non—small cell lung cancer with an acquired MET exon 14 skipping mutation mediated resistance to alectinib: a case report [J]. Transl Lung Cancer Res, 2023, 12(12): 2558-2564.

[27] Gonzalez—Martinez D, Roth L, Mumford T R, et al. Oncogenic EML4—ALK assemblies suppress growth factor perception and modulate drug tolerance [J]. Nat Commun, 2024, 15(1): 9473.

[28] Nakazawa M, Harada G, Ghanem P, et al. Impact of tumor—intrinsic molecular features on survival and acquired tyrosine kinase inhibitor resistance in ALK—positive NSCLC [J]. Cancer Res Commun, 2024, 4(3): 786-795.

[29] Villa M, Malighetti F, Sala E, et al. New pan—ALK inhibitor—resistant EML4: ALK mutations detected by liquid biopsy in lung cancer patients [J]. NPJ Precis Oncol, 2024, 8(1): 29.

[30] Diaz—Jimenez A, Ramos M, Helm B, et al. Concurrent inhibition of ALK and SRC kinases disrupts the ALK lung tumor cell proteome [J]. Drug Resist Updat, 2024, 74: 101081.

[31] Hu Q Q, Remsing Rix L L, Desai B, et al. Cancer—associated fibroblasts confer ALK inhibitor resistance in EML4—ALK—driven lung cancer via concurrent integrin and MET signaling [J]. bioRxiv, doi: 10.1101/2024.08.27.609975.

[32] Qin Z, Sun H, Yue M, et al. Phase separation of EML4—ALK in firing downstream signaling and promoting lung tumorigenesis [J]. Cell Discov, 2021, 7(1): 33.

[33] Qin Z, Yue M, Tang S, et al. EML4—ALK fusions drive lung adeno—to—squamous transition through JAK—STAT activation [J]. J Exp Med, 2024, 221(3): e20232028.

[34] 杨燕, 陈丹, 朱红革. 非小细胞肺癌中免疫检查点及免疫治疗中细胞亚群的异质性 [J]. 国际老年医学杂志, 2024, 45(6): 653-661.

[35] Yang Y, Chen D, Zhu H G , Study on the Heterogeneity of cell subpopulations in immunotherapy and immune checkpoints in non—small cell lung cancer [J]. Int J Geriatr, 2024, 45(6): 653-661.

[36] Desai A, Lovly C M. Strategies to overcome resistance to ALK inhibitors in non—small cell lung cancer: a narrative review [J]. Transl Lung Cancer Res, 2023, 12(3): 615-628.

[37] Marrugal Á, Ferrer I, Quintanal—Villalonga Á, et al. Inhibition of HSP90 in driver oncogene—defined lung adenocarcinoma cell lines: key proteins underpinning therapeutic efficacy [J]. Int J Mol Sci, 2023, 24(18): 13830.

[38] Kim M, Ju H M, Song J Y, et al. HER3 overexpression: a predictive marker for poor prognosis in advanced ALK—positive non—small cell lung cancer treated with ALK inhibitors [J]. Transl Lung Cancer Res, 2024, 13(2): 321-333.

[39] Sampson J, Ju H M, Zhang N, et al. Targeting ERBB3 and AKT to overcome adaptive resistance in EML4—ALK—driven non—small cell lung cancer [J]. Cell Death Dis, 2024, 15(12): 912.

[40] Papageorgiou S, Pashley S L, O'Regan L, et al. Microtubule association of EML4—ALK V3 is key for the elongated cell morphology and enhanced migration observed in V3 Cells [J]. Cells, 2024, 13(23): 1954.

[41] Pashley S L, Papageorgiou S, O'Regan L, et al. The mesenchymal morphology of cells expressing the EML4—ALK V3 oncogene is dependent on phosphorylation of Eg5 by NEK7 [J]. J Biol Chem, 2024, 300(5): 107144.

[42] Kong S T, 杨永鹏, 张进芳, 等. 液体活检实时精准诊断老年肿瘤的临床应用价值 [J]. 国际老年医学杂志, 2020, 41(1): 50-56.

[43] Kong S T, Yang Y P, Zhang J F, et al. Application of liquid biopsy in real—time accurate diagnosis of tumor in the elderly [J]. Int J Geriatr, 2020, 41(1): 50-56.

[44] Arndt A, Neumann C, Riecke A, et al. Molecular tumor board: molecularly adjusted therapy upon identification and functional validation of a novel ALK resistance mutation in a case of lung adenocarcinoma [J]. Oncologist, 2025, 30(1): oyae143.

[45] Liang S K, Liao W Y, Shih J Y, et al. Clinical utility and predictive value of cerebrospinal fluid cell—free DNA profiling in non—small cell lung cancer patients with leptomeningeal metastasis [J]. Neoplasia, 2025, 60: 101113.

[46] Yang Y, Zhang Y, Zhou S, et al. Establishment of potential reference measurement procedure and reference materials for EML4—ALK fusion variants measurement [J]. Sci Rep, 2024, 14(1): 24543.

基金资助

^*山东省医药卫生科技项目(202302081053)

山东省教育厅2022年山东省研究生优质教育教学资源项目(SDYKC2022042)

山东省中医药管理局科技发展计划(2017-118)

山东省卫生计生委科技发展计划(2017WS600)