|
|
EGFR在肿瘤发生发展及治疗中的作用研究进展
|
Abstract:
表皮生长因子受体(Epidermal Growth Factor Receptor, EGFR)是一种关键的跨膜糖蛋白，广泛分布于人体各组织细胞膜上，其调控作用对于维持细胞的正常生理功能至关重要。科学研究表明，EGFR基因突变或表达水平异常升高可导致肿瘤的形成与扩散。自EGFR被发现以来，对其及其作用机制的研究已持续超过半个世纪，期间重大发现与突破不断涌现。本综述文章主要探讨了EGFR及其下游信号传导途径与肿瘤发生发展的关联，分析了以EGFR为靶点的肿瘤治疗药物，并对后续研究方向进行了客观的分析与展望。
The Epidermal Growth Factor Receptor (EGFR) is a key transmembrane glycoprotein that is widely distributed on cell membranes of various tissues in the human body. Its regulatory role is crucial to maintaining normal physiological functions of cells. Scientific research has shown that mutations or abnormally elevated expression levels of the EGFR gene can lead to the formation and spread of tumors. Since its discovery, research on EGFR and its mechanism of action has continued for more than half a century, during which major discoveries and breakthroughs have continued to emerge. This review article mainly discusses the relationship between EGFR and its downstream signal transduction pathways and tumor development, analyzes tumor therapeutic drugs targeting EGFR, and provides objective analysis and prospects for subsequent research directions.
| [1] | Xia, C.F., et al. (2022) Cancer Statistics in China and United States, 2022: Profiles, Trends, and Determinants. Chinese Medical Journal, 135, 584-590. |
| [2] | Rajaram, P., Chandra, P., Ticku, S., et al. (2017) Epidermal Growth Factor Receptor: Role in Human Cancer. Indian Journal of Dental Research, 28, 687-694. |
| [3] | Pan, P.C. and Magge, R.S. (2020) Mechanisms of EGFR Resistance in Glioblastoma. International Journal of Molecular Sciences, 21, Article No. 8471. https://doi.org/10.3390/ijms21228471 |
| [4] | 吴健虹, 谢秋玲, 陈小佳, 等. 表皮生长因子受体EGFR及其信号传导[J]. 生命科学, 2006, 18(2): 116-122. |
| [5] | 张锦锦, 唐慧. 表皮生长因子受体在肿瘤发生、发展中的研究进展[J]. 中国生物制品学杂志, 2018, 31(4): 425-430. |
| [6] | Ogiso, H., Ishitani, R., Nureki, O., Fukai, S., Yamanaka, M., Kim, J., et al. (2002) Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular Domains. Cell, 110, 775-787. https://doi.org/10.1016/s0092-8674(02)00963-7 |
| [7] | Schenk, E.L., Patil, T., Pacheco, J. and Bunn, P.A. (2020) 2020 Innovation-Based Optimism for Lung Cancer Outcomes. The Oncologist, 26, e454-e472. https://doi.org/10.1002/onco.13590 |
| [8] | Harrison, P.T., Vyse, S. and Huang, P.H. (2020) Rare Epidermal Growth Factor Receptor (EGFR) Mutations in Non-Small Cell Lung Cancer. Seminars in Cancer Biology, 61, 167-179. https://doi.org/10.1016/j.semcancer.2019.09.015 |
| [9] | Castellanos, E., Feld, E. and Horn, L. (2017) Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer. Journal of Thoracic Oncology, 12, 612-623. https://doi.org/10.1016/j.jtho.2016.12.014 |
| [10] | Yatabe, Y. (2010) EGFR Mutations and the Terminal Respiratory Unit. Cancer and Metastasis Reviews, 29, 23-36. https://doi.org/10.1007/s10555-010-9205-8 |
| [11] | Sabbah, D.A., Hajjo, R. and Sweidan, K. (2020) Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Current Topics in Medicinal Chemistry, 20, 815-834. https://doi.org/10.2174/1568026620666200303123102 |
| [12] | Seshacharyulu, P., Ponnusamy, M.P., Haridas, D., et al. (2012) Targeting the EGFR Signaling Pathway in Cancer Therapy. Expert Opinion on Therapeutic Targets, 27, 305-324. |
| [13] | Jorissen, R. (2003) Epidermal Growth Factor Receptor: Mechanisms of Activation and Signalling. Experimental Cell Research, 284, 31-53. https://doi.org/10.1016/s0014-4827(02)00098-8 |
| [14] | Wee, P. and Wang, Z. (2017) Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers, 9, Article No. 52. https://doi.org/10.3390/cancers9050052 |
| [15] | Khotskaya, Y.B., Holla, V.R., Farago, A.F., Mills Shaw, K.R., Meric-Bernstam, F. and Hong, D.S. (2017) Targeting TRK Family Proteins in Cancer. Pharmacology & Therapeutics, 173, 58-66. https://doi.org/10.1016/j.pharmthera.2017.02.006 |
| [16] | 孙栋勋, 综述, 蔡志毅, 审校. EGFR/PI3K/Akt细胞信号传导通路与肿瘤[J]. 检验医学, 2014(7): 768-773. |
| [17] | Mayer, I.A. and Arteaga, C.L. (2016) The PI3K/AKT Pathway as a Target for Cancer Treatment. Annual Review of Medicine, 67, 11-28. https://doi.org/10.1146/annurev-med-062913-051343 |
| [18] | Xue, C., Yao, Q., Gu, X., Shi, Q., Yuan, X., Chu, Q., et al. (2023) Evolving Cognition of the JAK-STAT Signaling Pathway: Autoimmune Disorders and Cancer. Signal Transduction and Targeted Therapy, 8, Article No. 204. https://doi.org/10.1038/s41392-023-01468-7 |
| [19] | 刘艳春, 贾儒渊, 樊志慧, 等. 表皮生长因子受体在食管鳞状细胞癌组织中的表达及其临床意义[J]. 临床误诊误治, 2024, 37(10): 35-38. |
| [20] | 李海斌, 吴振虎, 丁建峰. 肿瘤相关巨噬细胞内Notch-1通过抑制组织蛋白酶S过表达影响非小细胞肺癌腺癌侵袭转移的机制研究[J]. 临床误诊误治, 2024, 37(16): 88-95. |
| [21] | 吕蕾, 吕建. 顺铂联合多西他赛治疗非小细胞肺癌的临床疗效[J]. 临床合理用药杂志, 2022(4): 15. |
| [22] | Shi, Y., Au, J.S., Thongprasert, S., Srinivasan, S., Tsai, C., Khoa, M.T., et al. (2014) A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology (Pioneer). Journal of Thoracic Oncology, 9, 154-162. https://doi.org/10.1097/jto.0000000000000033 |
| [23] | Zhang, Y., Yuan, J., Wang, K., Fu, X., Han, X., Threapleton, D., et al. (2016) The Prevalence of EGFR Mutation in Patients with Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Oncotarget, 7, 78985-78993. https://doi.org/10.18632/oncotarget.12587 |
| [24] | Hsieh, R., Lim, K., Kuo, H., Tzen, C. and Huang, M. (2005) Female Sex and Bronchioloalveolar Pathologic Subtype Predict EGFR Mutations in Non-Small Cell Lung Cancer. Chest, 128, 317-321. https://doi.org/10.1378/chest.128.1.317 |
| [25] | Benbrahim, Z., Antonia, T. and Mellas, N. (2018) EGFR Mutation Frequency in Middle East and African Non-Small Cell Lung Cancer Patients: A Systematic Review and Meta-Analysis. BMC Cancer, 18, Article No. 891. https://doi.org/10.1186/s12885-018-4774-y |
| [26] | Batra, U., Biswas, B., Prabhash, K. and Krishna, M.V. (2023) Differential Clinicopathological Features, Treatments and Outcomes in Patients with Exon 19 Deletion and Exon 21 L858R EGFR Mutation-Positive Adenocarcinoma Non-Small-Cell Lung Cancer. BMJ Open Respiratory Research, 10, e001492. https://doi.org/10.1136/bmjresp-2022-001492 |
| [27] | Stintzing, S., Heinemann, V., Moosmann, N., et al. (2009) The Treatment of Colorectal Carcinoma with Monoclonal Antibodies: The Importance of KRAS Mutation Analysis and EGFR Status. Deutsches Arzteblatt International, 106, 202-206. |
| [28] | Guo, G., Gong, K., Beckley, N., Zhang, Y., Yang, X., Chkheidze, R., et al. (2022) EGFR Ligand Shifts the Role of EGFR from Oncogene to Tumour Suppressor in EGFR-Amplified Glioblastoma by Suppressing Invasion through BIN3 Upregulation. Nature Cell Biology, 24, 1291-1305. https://doi.org/10.1038/s41556-022-00962-4 |
| [29] | Kalyankrishna, S. and Grandis, J.R. (2006) Epidermal Growth Factor Receptor Biology in Head and Neck Cancer. Journal of Clinical Oncology, 24, 2666-2672. https://doi.org/10.1200/jco.2005.04.8306 |
| [30] | 王昕, 付洁, 严颐丹, 等. 新型抗肿瘤药物研究进展与临床应用[J]. 上海医药, 2022, 43(z2): 9-21. |
| [31] | Koulouris, A., Tsagkaris, C., Corriero, A.C., Metro, G. and Mountzios, G. (2022) Resistance to TKIs in EGFR-Mutated Non-Small Cell Lung Cancer: From Mechanisms to New Therapeutic Strategies. Cancers, 14, Article No. 3337. https://doi.org/10.3390/cancers14143337 |
| [32] | Amelia, T., Kartasasmita, R.E., Ohwada, T. and Tjahjono, D.H. (2022) Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors. Molecules, 27, Article No. 819. https://doi.org/10.3390/molecules27030819 |
| [33] | Tydings, C.W., Singh, B., Smith, A.W., Ledwitch, K.V., Brown, B.P., Lovly, C.M., et al. (2024) Analysis of EGFR Binding Hotspots for Design of New EGFR Inhibitory Biologics. Protein Science, 33, e5141. https://doi.org/10.1002/pro.5141 |
| [34] | Sun, R., Hou, Z., Zhang, Y. and Jiang, B. (2022) Drug Resistance Mechanisms and Progress in the Treatment of EGFR-Mutated Lung Adenocarcinoma (Review). Oncology Letters, 24, Article No. 408. https://doi.org/10.3892/ol.2022.13528 |
| [35] | Kitadai, R. and Okuma, Y. (2022) Treatment Strategies for Non-Small Cell Lung Cancer Harboring Common and Uncommon EGFR Mutations: Drug Sensitivity Based on Exon Classification, and Structure-Function Analysis. Cancers, 14, Article No. 2519. https://doi.org/10.3390/cancers14102519 |
| [36] | 巫建群. 某院非小细胞肺癌治疗中EGFR-TKI使用情况分析[J]. 海峡药学, 2024, 36(4): 70-73. |
| [37] | Ohashi, K., Suda, K., Sun, J., Pan, Y., Walter, A.O., Dubrovskiy, A., et al. (2013) Abstract 2101A: CNX-2006, a Novel Irreversible Epidermal Growth Factor Receptor (EGFR) Inhibitor, Selectively Inhibits EGFR T790M and Fails to Induce T790m-Mediated Resistance in Vitro. Cancer Research, 73, 2101A. https://doi.org/10.1158/1538-7445.am2013-2101a |
| [38] | Scalvini, L., Castelli, R., La Monica, S., Tiseo, M. and Alfieri, R. (2021) Fighting Tertiary Mutations in EGFR-Driven Lung-Cancers: Current Advances and Future Perspectives in Medicinal Chemistry. Biochemical Pharmacology, 190, Article ID: 114643. https://doi.org/10.1016/j.bcp.2021.114643 |
| [39] | Yonesaka, K., Kobayashi, Y., Hayashi, H., Chiba, Y., Mitsudomi, T. and Nakagawa, K. (2018) Dual Blockade of EGFR Tyrosine Kinase Using Osimertinib and Afatinib Eradicates EGFR-Mutant Ba/F3 Cells. Oncology Reports, 41, 1059-1066. https://doi.org/10.3892/or.2018.6881 |
| [40] | Bhanja, K.K., Sharma, M. and Patra, N. (2023) Uncovering the Structural and Binding Insights of Dual Inhibitors Simultaneously Targeting Two Distinct Sites on EGFR Kinase. The Journal of Physical Chemistry B, 127, 10749-10765. https://doi.org/10.1021/acs.jpcb.3c04337 |
| [41] | Fukuda, S., Suda, K., Hamada, A., Oiki, H., Ohara, S., Ito, M., et al. (2024) Potential Utility of a 4th-Generation EGFR-TKI and Exploration of Resistance Mechanisms—An in Vitro Study. Biomedicines, 12, Article No. 1412. https://doi.org/10.3390/biomedicines12071412 |
| [42] | Kasibhatla, S., Li, J., Tompkins, C., Vaillancourt, M., Anderson, J., Pferdekamper, A.C., et al. (2014) Abstract 1733: EGF816, a Novel Covalent Inhibitor of Mutant-Selective Epidermal Growth Factor Receptor, Overcomes T790m-Mediated Resistance in NSCLC. Cancer Research, 74, 1733-1733. https://doi.org/10.1158/1538-7445.am2014-1733 |
| [43] | Hirsh, V., Blais, N., Burkes, R., Verma, S. and Croitoru, K. (2014) Management of Diarrhea Induced by Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. Current Oncology, 21, 329-336. https://doi.org/10.3747/co.21.2241 |
| [44] | Zhang, T., Qu, R., Chan, S., Lai, M., Tong, L., Feng, F., et al. (2020) Discovery of a Novel Third-Generation EGFR Inhibitor and Identification of a Potential Combination Strategy to Overcome Resistance. Molecular Cancer, 19, Article No. 90. https://doi.org/10.1186/s12943-020-01202-9 |
| [45] | Zhang, X., Maity, T.K., Ross, K.E., et al. (2020) Global Proteome and Phosphoproteome Alterations in Third Generation EGFR TKI Resistance Reveal Drug Targets to Circumvent Resistance. |
| [46] | Zhang, G., Yan, B., Guo, Y., Yang, H., Li, X. and Li, J. (2022) Case Report: A Patient with the Rare Third-Generation TKI-Resistant Mutation EGFR L718Q Who Responded to Afatinib plus Cetuximab Combination Therapy. Frontiers in Oncology, 12, Article ID: 995624. https://doi.org/10.3389/fonc.2022.995624 |
| [47] | 姜俊, 任新玲. 非小细胞肺癌EGFR-TKI耐药机制及应对策略研究进展[J]. 国际呼吸杂志, 2020, 40(1): 63-69. |
| [48] | Zhang, Y., Wang, C., Zhao, J. and Wang, M. (2024) The Efficacy of Almonertinib and Anlotinib Combination Therapy for Advanced Non-Small-Cell Lung Cancer Patients Who Continued to Experience Cancer Progression during Third‐Generation EGFR‐TKI Treatment: A Retrospective Study. Thoracic Cancer, 15, 1757-1763. https://doi.org/10.1111/1759-7714.15399 |
| [49] | Zhang, Y., Tong, L., Yan, F., Huang, P., Zhu, C. and Pan, C. (2024) Design, Synthesis, and Antitumor Activity Evaluation of Potent Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib Resistant Non-Small Cell Lung Cancer (NSCLC). Bioorganic Chemistry, 147, Article ID: 107394. https://doi.org/10.1016/j.bioorg.2024.107394 |
| [50] | Wang, S., Song, Y. and Liu, D. (2017) EAI045: The Fourth-Generation EGFR Inhibitor Overcoming T790M and C797S Resistance. Cancer Letters, 385, 51-54. https://doi.org/10.1016/j.canlet.2016.11.008 |
| [51] | Heinz-Josef, L. (2006) Anti-EGFR Mechanism of Action: Antitumor Effect and Underlying Cause of Adverse Events. Oncology, 20, 5-13. |
| [52] | Li, Q.-H., et al. (2020) Anti-EGFR Therapy in Metastatic Colorectal Cancer: Mechanisms and Potential Regimens of Drug Resistance. Gastroenterology Report (Oxford), 8, 179-191. |
| [53] | 周建宇, 秦晓红, 米立志. 第三代EGFR-TKI耐药性机制及联合用药治疗的策略[J]. 中国生物化学与分子生物学报, 2024, 40(2): 170-179. |
| [54] | 王昭卜, 黎星, 于鑫淼, 等. 2023年改变早期乳腺癌临床实践的重要研究成果及进展[J]. 中国癌症杂志, 2024, 34(2): 151-160. |
