肺癌是全球范围内癌症首位致死率的恶性肿瘤,其中主要为非小细胞肺癌(NSCLC)。肺癌各类小分子靶标已经成为靶向药物研发和临床治疗的研究热点,以表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)等为代表的分子靶向药物通过阻止重要细胞信号传递,遏制肿瘤细胞生长增殖从而控制癌症进展。本文主要综述目前NSCLC中明确的分子途径及相应分子靶向治疗药物的进展。
Lung cancer is a malignant tumor with the highest mortality in the world, and non-small cell lung cancer (NSCLC) is the most common type. There are more and more researches on molecular targets for lung cancer, leading to the rapid development of various molecular targeted drugs. Molecular targeted drugs such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR- TKI) block important pathways that drive cancer progression and achieve long-term disease control. This review summarizes the most important molecular pathways in NSCLC and describes the development of therapeutic drugs against these targets.
Lung cancer is a malignant tumor with the highest mortality in the world, and non-small cell lung cancer (NSCLC) is the most common type. There are more and more researches on molecular targets for lung cancer, leading to the rapid development of various molecular targeted drugs. Molecular targeted drugs such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) block important pathways that drive cancer progression and achieve long-term disease control. This review summarizes the most important molecular pathways in NSCLC and describes the development of therapeutic drugs against these targets.
第三代EGFR-TKI是选择性高的不可逆TKI,尤其适用于T790M突变,如奥西替尼(Osimertinib),但最终结局也会产生耐药。奥西替尼的耐药机制主要包括EGFR发生C797S突变、MET等促癌基因异常、HER2扩增等旁路突变和组织学转变等。常见不良反应包括胃肠功能紊乱、丘疹和间质性肺病。阿美替尼(Almonertinib)是我国自主研发的首个获批创上市的新型第三代EGFR-TKI,于2020年3月正式获批 [13]。我国自主研发的伏美替尼(Furmonertinib)在2021年随即获批上市 [14]。第三代EGFR-TKI可通过血脑屏障,也用于治疗他突变亚型,以奥希替尼为主的三代TKIs在EGFR突变晚期NSCLC治疗中的确切疗效及良好的安全性,尤其在中枢神经系统转移和19缺失突变的患者中具有显著优势,美国国立综合癌症网络(National Comprehensive Cancer Network, NCCN)和欧洲肿瘤医学会(European Society for Medical Oncology, ESMO)等多国指南均将第三代靶向药物奥希替尼作为NSLCL一线治疗首选推荐的药物 [3] [4]。
点突变、融合突变和过度表突变是ALK基因主要突变形式。研究发现,目前在多于90个融合基因的ALK阳性NSCLC中,最常见的融合发生于ALK基因的20~29号外显子与棘皮动物微管相关类蛋白(Echinoderm microtubule-associated protein like 4, EML4-ALK)基因的1~13号外显子,发生率占5%~6% [19]。EML4-ALK基因融合导致编码跨膜酪氨酸激酶受体的ALK基因持续表达,从而持续激活ALK酪氨酸激酶区及下游Ras/MAPK、PI3K/AKT和JAK/STAT等信号通路,促进细胞增殖和分化,产生癌变 [22]。ALK基因重排患者对EGFR-TKIs治疗不敏感,而EML4-ALK作为ALK抑制剂的靶点在ALK阳性NSCLC患者的疗效得到证实 [23],目前TKI是ALK融合基因阳性NSCLC患者的一线辅助治疗方法 [3]。
申 越,王 睿,高 婧,尹 楠,王文杰,曹荣月. 非小细胞肺癌小分子的靶向治疗研究进展Research Progress on Small Molecules Targeted Therapy in Non-Small Cell Lung Cancer[J]. 世界肿瘤研究, 2022, 12(02): 90-98. https://doi.org/10.12677/WJCR.2022.122012
参考文献ReferencesSung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249.
https://doi.org/10.3322/caac.21660刘宗超, 李哲轩, 张阳, 等. 2020全球癌症统计报告解读[J]. 肿瘤综合治疗电子杂志, 2021, 7(2): 1-14.NCCN Clinical Practice Guidelines in Oncology (2021) Non-Small Cell Lung Cancer.
https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450Planchard, D., Popat, S., Kerr, K., et al. (2018) Metastatic Non-Small Cell Lung Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Annals of Oncology, 29, iv192-iv237.
https://doi.org/10.1093/annonc/mdy275中国临床肿瘤学会(CSCO). 非小细胞肺癌诊疗指南(2021) [M]. 北京: 人民卫生出版社, 2021.Ohe, Y., Imamura, F., Nogami, N., et al. (2019) Osimertinib versus Standard-of-Care EGFR-TKI as First-Line Treatment for EGFRm Advanced NSCLC: FLAURA Japanese Subset. Japanese Journal of Clinical Oncology, 49, 29-36. https://doi.org/10.1093/jjco/hyy179Shaw, A.T., Bauer, T.M., De Marinis, F., et al. (2020) First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. The New England Journal of Medicine, 383, 2018-2029. https://doi.org/10.1056/NEJMoa2027187Rotow, J. and Bivona, T.G. (2017) Understanding and Targeting Resistance Mechanisms in NSCLC. Nature Reviews Cancer, 17, 637-658. https://doi.org/10.1038/nrc.2017.84Shi, H., Zhang, T., Yi, Y., et al. (2016) Inhibition of the Ras-ERK Pathway in Mitotic COS7 Cells Is Due to the Inability of EGFR/Raf to Transduce EGF Signaling to Downstream Proteins. Oncology Reports, 35, 3593-3599.
https://doi.org/10.3892/or.2016.4696Sharma, S.V., Bell, D.W., Settleman, J., et al. (2007) Epidermal Growth Factor Receptor Mutations in Lung Cancer. Nature Reviews Cancer, 7, 169-181. https://doi.org/10.1038/nrc2088Wu, Y.L., Cheng, Y., Zhou, X., et al. (2017) Dacomitinib versus Gefitinib as First-Line Treatment for Patients with EGFR-Mutation-Positive Non-Small-Cell Lung Cancer (ARCHER 1050): A Randomised, Open-Label, Phase 3 Trial. The Lancet Oncology, 18, 1454-1466. https://doi.org/10.1016/S1470-2045(17)30608-3Tamiya, A., Tamiya, M., Nishihara, T., et al. (2017) Cerebrospinal Fluid Penetration Rate and Efficacy of Afatinib in Patients with EGFR Mutation-Positive Non-Small Cell Lung Cancer with Leptomeningeal Carcinomatosis: A Multicenter Prospective Study. Anticancer Research, 37, 4177-4182. https://doi.org/10.21873/anticanres.11806国家药监局. 国家药监局批准甲磺酸阿美替尼片上市[EB/OL]. 2020-03-31.
https://www.nmpa.gov.cn/yaopin/ypjgdt/20200331172101492.html, 2022-03-24.国家药监局. 国家药监局附条件批准甲磺酸伏美替尼片上市[EB/OL]. 2021-03-03.
https://www.nmpa.gov.cn/yaowen/ypjgyw/20210303144734196.html, 2022-03-24.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.2016.11.008Jänne, P.A., Baik, C., Su, W.C., et al. (2022) Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer. Cancer Discovery, 12, 74-89.
https://doi.org/10.1158/2159-8290.CD-21-0715Kashima, K., Kawauchi, H., Tanimura, H., et al. (2020) CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/ T790M/C797S Mutation. Molecular Cancer Therapeutics, 19, 2288-2297.
https://doi.org/10.1158/1535-7163.MCT-20-0229Hanna, N., Johnson, D., Temin, S., et al. (2017) Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Thoracic Oncology, 35, 3484-3515.
https://doi.org/10.1200/JCO.2017.74.6065Soda, M., Choi, Y.L., Enomoto, M., et al. (2007) Identification of the Transforming EML4-ALK Fusion Gene in Non- Small-Cell Lung Cancer. Nature, 448, 561-566. https://doi.org/10.1038/nature05945张连美, 仲纪祥, 孙苏安. EGFR、ALK和Ki-67在非小细胞肺癌中的表达及相关性分析[J]. 临床肺科杂志, 2017, 22(1): 4-7.Morris, S.W., Naeve, C., Mathew, P., et al. (1997) ALK, the Chromosome 2 Gene Locus Altered by the t(2;5) in Non- Hodgkin’s Lymphoma, Encodes A Novel Neural Receptor Tyrosine Kinase That Is Highly Related to Leukocyte Tyrosine Kinase (LTK). Oncogene, 14, 2175-2188. https://doi.org/10.1038/sj.onc.1201062贺荣芝, 刘川, 蔡婧, 等. 非小细胞肺癌EGFR、ALK、ROS1基因突变和临床病理特征分析[J]. 临床与实验病理学杂志, 2019, 35(7): 843-845.Pan, Y., Deng, C., Qiu, Z., et al. (2021) The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer. Frontiers in Oncology, 11, Article No. 804. https://doi.org/10.3389/fonc.2021.713530张绪超, 陆舜, 张力, 等. 中国间变性淋巴瘤激酶(ALK)阳性非小细胞肺癌诊断专家共识(2013版) [J]. 中华病理学杂志, 2013, 42(6): 402-406.汪洋, 袁晓玢, 熊佳艳, 等. 盐酸恩沙替尼胶囊的药理与临床评价[J]. 中国肺癌杂志, 2020, 23(8): 719-729.国家药监局. 国家药监局批准盐酸恩沙替尼胶囊上市[EB/OL]. 2020-11-20.
https://www.nmpa.gov.cn/yaopin/ypjgdt/20201120154321135.html, 2022-03-24.U.S. Food and Drug Administration (2021) FDA Approves Lorlatinib for Metastatic ALK-Positive NSCLC.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lorlatinib-metastatic-alk-positive-nsclcRimkunas, V.M., Crosby, K.E., Li, D., et al. (2012) Analysis of Receptor Tyrosine Kinase ROS1-Positive Tumors in Non-Small Cell Lung Cancer: Identification of a FIG-ROS1 Fusion. Clinical Cancer Research, 18, 4449-4457.
https://doi.org/10.1158/1078-0432.CCR-11-3351Bergethon, K., Shaw, A.T., Ou, S.H., et al. (2012) ROS1 Rearrangements Define a Unique Molecular Class of Lung Cancers. Journal of Clinical Oncology, 30, 863-870. https://doi.org/10.1200/JCO.2011.35.6345Xu, Y., Chang, H., Wu, L., et al. (2020) High Prevalence of ROS1 Gene Rearrangement Detected by FISH in EGFR and ALK Negative Lung Adenocarcinoma. Experimental and Molecular Pathology, 117, Article ID: 104548.
https://doi.org/10.1016/j.yexmp.2020.104548Park, S., Ahn, B.C., Lim, S.W., et al. (2018) Characteristics and Outcome of ROS1-Positive Non-Small Cell Lung Cancer Patients in Routine Clinical Practice. Journal of Thoracic Oncology, 13, 1373-1382.
https://doi.org/10.1016/j.jtho.2018.05.026Drilon, A., Ou, S.I., Cho, B.C., et al. (2018) Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent-Front Mutations. Cancer Discovery, 8, 1227-1236.
https://doi.org/10.1158/2159-8290.CD-18-0484Solomon, B.J., Besse, B., Bauer, T.M., et al. (2018) Lorlatinib in Patients with ALK-Positive Non-Small-Cell Lung Cancer: Results from a Global Phase 2 Study. The Lancet Oncology, 19, 1654-1667.
https://doi.org/10.1016/S1470-2045(18)30649-1Ou, S.I., Fujiwara, Y., Shaw, A.T., et al. (2021) Efficacy of Taletrectinib (AB-106/DS-6051b) in ROS1+ NSCLC: An Updated Pooled Analysis of U.S. and Japan Phase 1 Studies. JTO Clinical and Research Reports, 2, Article ID: 100108.
https://doi.org/10.1016/j.jtocrr.2020.100108Ji, H., Wang, Z., Perera, S.A., et al. (2007) Mutations in BRAF and KRAS Converge on Activation of the Mitogen- Activated Protein Kinase Pathway in Lung Cancer Mouse Models. Cancer Research, 67, 4933-4939.
https://doi.org/10.1158/0008-5472.CAN-06-4592Roviello, G., D’angelo, A., Sirico, M., et al. (2021) Advances in Anti-BRAF Therapies for Lung Cancer. Investigational New Drugs, 39, 879-890. https://doi.org/10.1007/s10637-021-01068-8Dienstmann, R. and Tabernero, J. (2011) BRAF as a Target for Cancer Therapy. Anti-Cancer Agents in Medicinal Chemistry, 11, 285-295. https://doi.org/10.2174/187152011795347469Kris, M.G., Johnson, B.E., Berry, L.D., et al. (2014) Using Multiplexed Assays of Oncogenic Drivers in Lung Cancers to Select Targeted Drugs. JAMA, 311, 1998-2006. https://doi.org/10.1001/jama.2014.3741赵媛媛, 周建英, 范云, 等. BRAF V600突变型非小细胞肺癌的治疗进展[J]. 中国癌症杂志, 2021, 31(12): 1145-1152.Facchinetti, F., Lacroix, L., Mezquita, L., et al. (2020) Molecular Mechanisms of Resistance to BRAF and MEK Inhibitors in BRAF (V600E) Non-Small Cell Lung Cancer. European Journal of Cancer, 132, 211-223.
https://doi.org/10.1016/j.ejca.2020.03.025孟雨菡, 刘素丽, 张会勇, 等. 重组GFP-VEGF6a融合肽的构建表达及其抗肿瘤活性[J]. 中国药科大学学报, 2011, 42(1): 83-87.Gianni, C., Bronte, G., Delmonte, A., et al. (2021) Case Report: Stevens-Johnson Syndrome and Hepatotoxicity Induced by Osimertinib Sequential to Pembrolizumab in a Patient With EGFR-Mutated Lung Adenocarcinoma. Frontiers in Pharmacology, 12, Article ID: 672233. https://doi.org/10.3389/fphar.2021.672233Schoenfeld, A.J., Arbour, K.C., Rizvi, H., et al. (2019) Severe Immune-Related Adverse Events Are Common with Sequential PD-(L)1 Blockade and Osimertinib. Annals of Oncology, 30, 839-844.
https://doi.org/10.1093/annonc/mdz077U.S. Food and Drug Administration (2021) FDA Grants Accelerated Approval to Sotorasib for KRAS G12C Mutated NSCLC.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc