酪氨酸激酶抑制剂在肝癌治疗中的耐药现状

摘要/Abstract

摘要： 酪氨酸激酶抑制剂(TKI)在肝癌治疗中应用广泛,但耐药问题限制了其长期疗效。本文系统综述了索拉非尼、仑伐替尼、瑞戈非尼等常用TKI在肝癌中的耐药机制,涵盖信号通路异常、基因突变、肿瘤微环境改变、免疫抑制、代谢重编程等。此外,文章探讨了联合免疫检查点抑制剂用药、针对耐药标志物HECTD2个体化治疗及开发新药等主要应对策略,旨在深入理解耐药机制并发展针对性干预手段,以期提高TKI治疗效果与患者预后。

刘雨, 周桂英, 孙涛, 张权. 酪氨酸激酶抑制剂在肝癌治疗中的耐药现状[J]. 肝脏, 2026, 31(7): 1048-1051.

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参考文献

[1] Yang Y, Li S, Wang Y, et al. Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective[J]. Signal Transduct Target Ther, 2022, 7(1): 329.
[2] Li J, Gong C, Zhou H, et al. Kinase inhibitors and kinase-targeted cancer therapies: recent advances and future perspectives[J]. Int J Mol Sci, 2024, 25(10): 5489.
[3] Llovet J M, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008, 359(4): 378-390.
[4] Cheng A L, Kang Y K, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase Ⅲ randomised, double-blind, placebo-controlled trial[J]. Lancet Oncol, 2009, 10(1): 25-34.
[5] Straś W, Gotlib J, Małkowski P, et al. Overall survival in patients with hepatocellular carcinoma treated with sorafenib: a polish experience[J]. Med Sci Monit, 2021, 27: e931856.
[6] Matter M S, Decaens T, Andersen J B, et al. Targeting the mTOR pathway in hepatocellular carcinoma: current state and future trends[J]. J Hepatol, 2014, 60(4): 855-865.
[7] Zhu Y, Zheng B, Wang H Y, et al. New knowledge of the mechanisms of sorafenib resistance in liver cancer[J]. Acta Pharmacol Sin, 2017, 38(5): 614-622.
[8] Sun M, Zhang Z, Chen C, et al. Exploring the potential mechanisms of sorafenib resistance in hepatocellular carcinoma cell lines based on RNA sequencing[J]. Cancer Cell Int, 2025, 25(1): 91.
[9] Yang Q, Cui M, Wang J, et al. Circulating mitochondrial DNA promotes M2 polarization of tumor associated macrophages and HCC resistance to sorafenib[J]. Cell Death Dis, 2025, 16(1): 153.
[10] Zhou S L, Zhou Z J, Hu Z Q, et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib[J]. Gastroenterology, 2016, 150(7): 1646-1658.
[11] Kudo M, Finn R S, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial[J]. Lancet, 2018, 391(10126): 1163-1173.
[12] Finn R S, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma[J]. N Engl J Med, 2020, 382(20): 1894-1905.
[13] 姚晓萌, 孙可可, 林云凯, 等. 肝细胞癌仑伐替尼耐药的分子机制[J]. 临床肝胆病杂志, 2024, 40(12): 2524-2530.
[14] Qin Y, Han S, Yu Y, et al. Lenvatinib in hepatocellular carcinoma: resistance mechanisms and strategies for improved efficacy[J]. Liver Int. 2024 44(8):1808-1831.
[15] Dong R, Fei Y, He Y, et al. Lactylation‐driven HECTD2 limits the response of hepatocellular carcinoma to lenvatinib[J]. Adv Sci, 2025,12(15): 2412559.
[16] de la Vega M R, Chapman E, Zhang D D. NRF2 and the hallmarks of cancer[J]. Cancer cell, 2018, 34(1): 21-43.
[17] Tang L, Ji Y, Ni C, et al. EIF4A3‐mediated biogenesis of CircFADS1 promotes the progression of hepatocellular carcinoma via Wnt/β-catenin pathway[J]. Adv Sci(Weinh), 2025,12(14): 2411869.
[18] Zucman-Rossi J, Villanueva A, Nault J C, et al. Genetic landscape and biomarkers of hepatocellular carcinoma[J]. Gastroenterology, 2015, 149(5): 1226-1239.
[19] Shen S, Faouzi S, Souquere S, et al. Melanoma persister cells are tolerant to BRAF/MEK inhibitors via ACOX1-mediated fatty acid oxidation[J]. Cell Rep, 2020, 33(8):108421.
[20] 奇卓然, 杜晓静, 杨毕伟, 等. 肝细胞癌仑伐替尼耐药机制与新治疗策略[J]. 中国临床医学, 2023, 30(02): 335-342.
[21] Rimassa L, Danesi R, Pressiani T, et al. Management of adverse events associated with tyrosine kinase inhibitors: improving outcomes for patients with hepatocellular carcinoma[J]. Cancer Treat Rev, 2019, 77: 20-28.
[22] 陈卫波, 蔡辉华, 杨岳, 等. 瑞戈非尼治疗肝细胞癌的研究进展[J]. 临床肝胆病杂志, 2017, 33(12): 2425-2428.
[23] Zhou H M, Chen D H, Diao W J, et al. Inhibition of RhoGEF/RhoA alleviates regorafenib resistance and cancer stemness via Hippo signaling pathway in hepatocellular carcinoma[J]. Exp Cell Res, 2024, 436(1): 113956.
[24] Driskill J H, Pan D. Control of stem cell renewal and fate by YAP and TAZ[J]. Nat Rev Mol Cell Biol, 2023, 24(12): 895-911.
[25] 陈坤. 通过 CRISPR/Cas9 全基因组敲除技术筛选瑞戈非尼在肝癌治疗中产生的耐药基因[D]. 厦门:厦门大学,2024.
[26] Zhu A X, Abbas A R, De Galarreta M R, et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma[J]. Nat Med, 2022, 28(8): 1599-1611.
[27] Bang Y H, Lee C, Yoo C, et al. Real-world efficacy and safety of cabozantinib in Korean patients with advanced hepatocellular carcinoma: a multicenter retrospective analysis[J]. Ther Adv Med Oncol, 2022, 14: 17588359221097934.
[28] Goyal L, Shi L, Liu L Y, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma[J]. Cancer Discov, 2019, 9(8): 1064-1079.
[29] Xiang Q, Chen W, Ren M, et al. Cabozantinib suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of VEGFR2 and MET[J]. Clin Cancer Res, 2014, 20(11): 2959-2970.
[30] 弓磊, 吴志浩, 周清华.STAT3在肿瘤侵袭转移中的作用[J]. 中国肺癌杂志,2010,13(10):980-984.
[31] Sumi T, Koshshino Y, Sekikawa M, et al. Risk factors for severe immune-related adverse events after first-line pembrolizumab monotherapy or combination chemotherapy for nonsmall-cell lung cancer[J]. Invest New Drugs, 2022, 40(6): 1298-1305.
[32] 杨芙蓉, 张雨婷, 陈志鹏, 等. 肿瘤代谢介导的免疫逃逸及血管生成研究进展[J]. 中国药理学通报, 2021, 37(6): 756-760.
[33] Qin S, Bi F, Gu S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase Ⅱ-Ⅲ trial[J]. J Clin Oncol, 2021, 39(27): 3002-3011.
[34] Yang C, Zhang H, Zhang L, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2023,20(4):203-222.
[35] Hou X, Xu Q, Liu R. CREB3 facilitates Donafenib resistance in hepatocellular carcinoma cells via the LSD1/CoREST/p65 axis by transcriptionally activating long noncoding RNA ZFAS1[J]. Transl Oncol, 2024, 44: 101684.
[36] Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study[J]. Lancet Oncol, 2021, 22(7): 977-990.
[37] Huang J, Guo Y, Huang W, et al. Regorafenib combined with PD-1 blockade immunotherapy versus regorafenib as second-line treatment for advanced hepatocellular carcinoma: a multicenter retrospective study[J]. J Hepatocell Carcinoma, 2022,9: 157-170.
[38] Wang X Y, Liao Y, Wang R Q, et al. Tribbles pseudokinase 3 converts sorafenib therapy to neutrophil-mediated lung metastasis in hepatocellular carcinoma[J]. Adv Sci, 2025,12(13): 2413682.
[39] Xu J, Wan Z, Tang M, et al. N6-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling[J]. Molecular cancer, 2020, 19(1):163.