肝细胞癌对仑伐替尼耐药机制的研究进展

摘要/Abstract

摘要： 肝细胞癌（hepatocellular carcinoma,HCC）是全球癌症相关死亡的主要原因之一。仑伐替尼（lenvatinib）是一种多激酶抑制剂,2018年被批准用于不可切除的HCC的一线治疗。然而仑伐替尼不可避免的耐药性是阻碍其长期抗癌活性的主要原因,其耐药机制尚未完全明确。本文依据信号通路及作用靶点分类,对HCC对仑伐替尼潜在的耐药机制进行了综述,为预防或延迟仑伐替尼耐药性的研究提供参考。

关键词: 肝细胞癌, 仑伐替尼, 耐药机制

Abstract: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lenvatinib is an inhibitor of multiple receptor tyrosine kinases, was approved in 2018 for the first-line treatment of unresectable HCC. However, the inevitable drug resistance of lenvatinib is the main reason that hindering its long-term anticancer activity, but the mechanism of drug resistance is not completely clear. In this paper, the potential mechanisms of resistance to lenvatinib in HCC were reviewed according to signal pathway and targets classification, providing reference for research on prevention or delay of lenvatinib resistance.

Key words: Hepatocellular carcinoma, Lenvatinib, Mechanism of drug resistance

张丽莎, 康明佳, 赵健. 肝细胞癌对仑伐替尼耐药机制的研究进展[J]. 肝癌电子杂志, 2023, 10(2): 37-40.

Zhang Lisha, Kang Mingjia, Zhao Jian. Progress on the mechanism of lenvatinib resistance in hepatocellular carcinoma[J]. Electronic Journal of Liver Tumor, 2023, 10(2): 37-40.

参考文献

[1] ZHAO Y, ZHANG Y N, WANG K T, et al.Lenvatinib for hepatocellular carcinoma: From preclinical mechanisms to anti-cancer therapy[J]. Biochim Biophys Acta Rev Cancer, 2020, 1874(1): 188391.
[2] CALO C A, LEVINE M D, BROWN M D, et al.Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series[J]. Gynecol Oncol Rep, 2023, 46: 101171.
[3] MIYAZAKI K, MORINE Y, XU C, et al.Curcumin-Mediated Resistance to Lenvatinib via EGFR Signaling Pathway in Hepatocellular Carcinoma[J]. Cells, 2023, 12(4): 612.
[4] TAN T, LIN X, LING J, et al.Case report: Abolishing primary resistance to PD-1 blockade by short-term treatment of lenvatinib in a patient with advanced metastatic renal cell carcinoma[J]. Front Immunol, 2023, 14: 1115691.
[5] HAO Z, WANG P.Lenvatinib in Management of Solid Tumors[J]. Oncologist, 2020, 25(2): e302-e310.
[6] 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.
[7] MAKKER V, TAYLOR M H, AGHAJANIAN C, et al.Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer[J]. J Clin Oncol, 2020, 38(26): 2981-2992.
[8] TAYLOR M H, LEE C H, MAKKER V, et al.Phase ⅠB/Ⅱ Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors[J]. J Clin Oncol, 2020, 38(11): 1154-1163.
[9] GUO B, CHEN Q, LIU Z, et al.Adjuvant therapy following curative treatments for hepatocellular carcinoma: current dilemmas and prospects[J]. Front Oncol, 2023, 13: 1098958.
[10] SUNG H, FERLAY J, SIEGEL R L, et al.Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[11] XU X, JIANG W, HAN P, et al.MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells by Downregulating c-Met[J]. J Hepatocell Carcinoma, 2022, 9: 113-126.
[12] 刘晓民, 孙巍, 魏建莹, 等. 仑伐替尼治疗酪氨酸激酶抑制剂经治不可切除肝细胞癌患者的效果及安全性观察[J]. 临床肝胆病杂志, 2022, 38(6): 1323-1327.
[13] JIN H, SHI Y, LV Y, et al.EGFR activation limits the response of liver cancer to lenvatinib[J]. Nature, 2021, 595(7869): 730-734.
[14] HE X, HIKIBA Y, SUZUKI Y, et al.EGFR inhibition reverses resistance to lenvatinib in hepatocellular carcinoma cells[J]. Sci Rep, 2022, 12(1): 8007.
[15] LIM M, FRANSES J W, IMPERIAL R, et al.EGFR/ERBB2 Amplifications and Alterations Associated With Resistance to Lenvatinib in Hepatocellular Carcinoma[J]. Gastroenterology, 2023, 164(6): 1006-1008.
[16] HUANG M, LONG J, YAO Z, et al.METTL1-Mediated m7G tRNA Modification Promotes Lenvatinib Resistance in Hepatocellular Carcinoma[J]. Cancer Res, 2023, 83(1): 89-102.
[17] ZHAO Z, ZHANG D, WU F, et al.Sophoridine suppresses lenvatinib-resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression[J]. J Cell Mol Med, 2021, 25(1): 549-560.
[18] LU Y, SHEN H, HUANG W, et al.Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance[J]. Cell Death Discov, 2021, 7(1): 359.
[19] FU R, JIANG S, LI J, et al.Activation of the HGF/c-MET axis promotes lenvatinib resistance in hepatocellular carcinoma cells with high c-MET expression[J]. Med Oncol, 2020, 37(4): 24.
[20] HOU W, BRIDGEMAN B, MALNASSY G, et al.Integrin subunit beta 8 contributes to lenvatinib resistance in HCC[J]. Hepatol Commun, 2022, 6(7): 1786-1802.
[21] MA X L, HU B, TANG W G, et al.CD73 sustained cancer-stem-cell traits by promoting SOX9 expression and stability in hepatocellular carcinoma[J]. J Hematol Oncol, 2020, 13(1): 11.
[22] QIN Y, QIAO Y, WANG D, et al.Ferritinophagy and ferroptosis in cardiovascular disease: Mechanisms and potential applications[J]. Biomed Pharmacother, 2021, 141: 111872.
[23] LI J, CAO F, YIN H L, et al.Ferroptosis: past, present and future[J]. Cell Death Dis, 2020, 11(2): 88.
[24] HANGAUER M J, VISWANATHAN V S, RYAN M J, et al.Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition[J]. Nature, 2017, 551(7679): 247-250.
[25] HONG X, ROH W, SULLIVAN R J, et al.The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis[J]. Cancer Discov, 2021, 11(3): 678-695.
[26] YANG C, ZHANG Y, LIN S, et al.Suppressing the KIF20A/NUAK1/Nrf2/GPX4 signaling pathway induces ferroptosis and enhances the sensitivity of colorectal cancer to oxaliplatin[J]. Aging (Albany NY), 2021, 13(10): 13515-13534.
[27] VISWANATHAN V S, RYAN M J, DHRUV H D, et al.Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway[J]. Nature, 2017, 547(7664): 453-457.
[28] ZHENG A, CHEVALIER N, CALDERONI M, et al.CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma[J]. Oncotarget, 2019, 10(66): 7058-7070.
[29] ISEDA N, ITOH S, TOSHIDA K, et al.Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor-4 inhibition in hepatocellular carcinoma[J]. Cancer Sci, 2022, 113(7): 2272-2287.
[30] LU T X, ROTHENBERG M E.MicroRNA[J]. J Allergy Clin Immunol, 2018, 141(4): 1202-1207.
[31] PENG W X, KOIRALA P, MO Y Y.LncRNA-mediated regulation of cell signaling in cancer[J]. Oncogene, 2017, 36(41): 5661-5667.
[32] WANG M, YU F, CHEN X, et al.The Underlying Mechanisms of Noncoding RNAs in the Chemoresistance of Hepatocellular Carcinoma[J]. Mol Ther Nucleic Acids, 2020, 21: 13-27.
[33] YU T, YU J, LU L, et al.MT1JP-mediated miR-24-3p/BCL2L2 axis promotes Lenvatinib resistance in hepatocellular carcinoma cells by inhibiting apoptosis[J]. Cell Oncol (Dordr), 2021, 44(4): 821-834.
[34] CHEN L, SHAN G.CircRNA in cancer: Fundamental mechanism and clinical potential[J]. Cancer Lett, 2021, 505: 49-57.
[35] ZHANG P, SUN H, WEN P, et al.circRNA circMED27 acts as a prognostic factor and mediator to promote lenvatinib resistance of hepatocellular carcinoma[J]. Mol Ther Nucleic Acids, 2022, 27: 293-303.
[36] WEI L, LEE D, LAW C T, et al.Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC[J]. Nat Commun, 2019, 10(1): 4681.
[37] EUN J W, YOON J H, AHN H R, et al.Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib[J]. Cancer Commun (Lond), 2023, 43(4): 455-479.
[38] MYOJIN Y, KODAMA T, MAESAKA K, et al.ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma[J]. Clin Cancer Res, 2021, 27(4): 1150-1161.
[39] WANG Z, SHEN J, CHEN C, et al.FOXA2 plays a critical role in hepatocellular carcinoma progression and lenvatinib-associated drug resistance[J]. Biosci Trends, 2023, 17(2): 136-147.
[40] ARECHEDERRA M, BAZAI S K, ABDOUNI A, et al.ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma[J]. J Hepatol, 2021, 74(4): 893-906.