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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 36 Issue 5
May  2020
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Article Contents

Mechanism and clinical effect of regorafenib in treatment of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2020.05.051
  • Published Date: 2020-05-20
  • As the first-line drug for the treatment of primary liver cancer, sorafenib has been widely used in clinical practice, but its drug resistance and toxic and side effects have become increasingly apparent, along with limited efficacy. In recent years, the research on regorafenib for the treatment of hepatocellular carcinoma(HCC) has gradually become a hotspot. The RESORCE trial has shown that regorafenib can significantly extend the overall survival time of patients with failed sorafenib treatment to 10.6 months, and regorafenib was approved as a second-line drug for advanced HCC by Food and Drug Administration in 2017. This article reviews the molecular mechanism, efficacy evaluation, combination therapy, and criteria for patient selection in the treatment of HCC with regorafenib, so as to provide a direction for further research in the future.

     

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  • [1] LLOVET JM, RICCI S, MAZZAFERRO V, et al. Sorafenib in advanced hepatocellular carcinoma[J]. N Engl J Med, 2008,359(4):378-390.
    [2] BRUIX J, QIN S, MERLE P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment(RESORCE):A randomised, double-blind, placebo-controlled, phase 3 trial[J]. Lancet, 2017, 389(10064):56-66.
    [3] FACCIORUSSO A, ABD El AZIZ MA, SACCO R. Efficacy of regorafenib in hepatocellular carcinoma patients:A systematic review and meta-analysis[J]. Cancers, 2020, 12(1):36.
    [4] TIETZE MK, WUESTEFELD T, PAUL Y, et al. IkappaBalpha gene therapy in tumor necrosis factor-alpha-and chemotherapy-mediated apoptosis of hepatocellular carcinomas[J]. Cancer Gene Ther, 2000, 7(10):1315-1323.
    [5] TSAI JJ, PAN PJ, HSU FT. Regorafenib induces extrinsic and intrinsic apoptosis through inhibition of ERK/NF-κB activation in hepatocellular carcinoma cells[J]. Oncol Rep, 2017, 37(2):1036-1044.
    [6] WENG MC, WANG MH, TSAI JJ, et al. Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice[J]. Biosci Rep,2018, 38(3):BSR20171264.
    [7] LIU YC, WU RH, WANG WS. Regorafenib diminishes the expression and secretion of angiogenesis and metastasis associated proteins and inhibits cell invasion via NF-κB inactivation in SK-Hep1 cells[J]. Oncol Lett, 2017, 14(1):461-467.
    [8] TAI WT, CHU PY, SHIAU CW, et al. STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma[J].Clin Cancer Res, 2014, 20(22):5768-5776.
    [9] GOTO K, ANNAN DA, MORITA T, et al. Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study[J]. Sci Rep, 2016, 6(1):38407.
    [10] ARAI J, GOTO K, STEPHANOU A, et al. Predominance of regorafenib over sorafenib:Restoration of membrane-bound MICA in hepatocellular carcinoma cells[J]. J Gastroenterol Hepatol, 2018, 33(5):1075-1081.
    [11] BRUIX J, TAK WY, GASBARRINI A, et al. Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma:Multicentre, open-label, phase II safety study[J]. Eur J Cancer, 2013, 49(16):3412-3419.
    [12] FINN RS, MERLE P, GRANITO A, et al. Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC:Additional analyses from the phase III RESORCE trial[J]. J Hepatol, 2018, 69(2):353-358.
    [13] YOO C, PARK JW, KIM YJ, et al. Multicenter retrospective analysis of the safety and efficacy of regorafenib after progression on sorafenib in Korean patients with hepatocellular carcinoma[J]. Invest New Drugs, 2019, 37(3):567-572.
    [14] OGASAWARA S, OOKA Y, ITOKAWA N, et al. Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma:A multicenter retrospective study in Japan[J]. Invest New Drugs, 2020, 38(1):172-180.
    [15] TEUFEL M, SEIDEL H, KÖCHERT K, et al. Biomarkers associated with response to regorafenib in patients with hepatocellular carcinoma[J]. Gastroenterology, 2019, 156(6):1731-1741.
    [16] XU Y, HUANG J, MA L, et al. MicroRNA-122 confers sorafenib resistance to hepatocellular carcinoma cells by targeting IGF-1R to regulate RAS/RAF/ERK signaling pathways[J].Cancer Lett, 2016, 371(2):171-181.
    [17] YANG Q, GUO X, YANG L. Metformin enhances the effect of regorafenib and inhibits recurrence and metastasis of hepatic carcinoma after liver resection via regulating expression of hypoxia inducible factors 2α(HIF-2α) and 30 kDa HIV tat-interacting protein(TIP30)[J]. Med Sci Monit, 2018, 24:2225-2234.
    [18] DONADON V, BALBI M, MAS MD, et al. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease[J]. Liver Int, 2010, 30(5):750-758.
    [19] SHIBUE T, WEINBERG RA. EMT, CSCs, and drug resistance:The mechanistic link and clinical implications[J]. Nat Rev Clin Oncol, 2017, 14(10):611-629.
    [20] ZHOU B, ZHAN H, TIN L, et al. TUFT1 regulates metastasis of pancreatic cancer through HIF1-Snail pathway induced epithelial-mesenchymal transition[J]. Cancer Lett, 2016,382(1):11-20.
    [21] LIU J, ZHU QM, HU HY, et al. Research advances in Hedgehog signaling pathway in hepatocellular carcinoma[J]. J Clin Hepatol, 2015, 31(2):300-304.(in Chinese)刘佳,朱琴梅,胡弘毅,等.Hedgehog信号通路在肝细胞癌发生发展中的作用[J].临床肝胆病杂志,2015, 31(2):300-304.
    [22] ZHENG X, VITTAR NB, GAI X, et al. The transcription factor GLI1 mediates TGFβ1 driven EMT in hepatocellular carcinoma via a SNAI1-dependent mechanism[J]. PLoS One, 2012, 7(11):e49581.
    [23] PU W, LI J, ZHENG Y, et al. Targeting Pin1 by inhibitor API-1 regulates microRNA biogenesis and suppresses hepatocellular carcinoma development[J]. Hepatology, 2018, 68(2):547-560.
    [24] LIAO XH, ZHANG AL, ZHENG M, et al. Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways[J]. Sci Rep, 2017, 7:43639.
    [25] WANG J, ZHANG N, HAN Q, et al. Pin1 inhibition reverses the acquired resistance of human hepatocellular carcinoma cells to Regorafenib via the Gli1/Snail/E-cadherin pathway[J]. Cancer Lett, 2019, 444:82-93.
    [26] TONG M, FUNG T, LUK T, et al. ANXA3/JNK Signaling promotes self-renewal and tumor growth, and its blockade provides a therapeutic target for hepatocellular carcinoma[J].Stem Cell Reports, 2015, 5(1):45-59.
    [27] TONG M, CHE N, ZHOU L, et al. Efficacy of annexin A3blockade in sensitizing hepatocellular carcinoma to sorafenib and regorafenib[J]. J Hepatol, 2018, 69(4):826-839.
    [28] TUTUSAUS A, STEFANOVIC M, BOIX L, et al. Antiapoptotic BCL-2 proteins determine sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma[J].Oncotarget, 2018, 9(24):16701-16717.
    [29] AMBROSIO S, AMENTE S, SACCÀCD, et al. LSD1 mediates MYCN control of epithelial-mesenchymal transition through silencing of metastatic suppressor NDRG1 gene[J]. Oncotarget, 2016, 8(3):3854-3869.
    [30] HUANG M, CHEN C, GENG J, et al. Targeting KDM1A attenuates Wnt/β-catenin signaling pathway to eliminate sorafenibresistant stem-like cells in hepatocellular carcinoma[J]. Cancer Lett, 2017, 398:12-21.
    [31] WU LW, ZHOU DM, ZHANG ZY, et al. Suppression of LSD1enhances the cytotoxic and apoptotic effects of regorafenib in hepatocellular carcinoma cells[J]. Biochem Biophys Res Commun, 2019, 512(4):852-858.
    [32] COMSTOCK CE, AUGELLO MA, GOODWIN JF, et al. Targeting cell cycle and hormone receptor pathways in cancer[J].Oncogene, 2013, 32(48):5481-5491.
    [33] XU J, HUANG F, YAO Z, et al. Inhibition of cyclin E1 sensitizes hepatocellular carcinoma cells to regorafenib by mcl-1suppression[J]. Cell Commun Signal, 2019, 17(1):85.
    [34] LIPPOLIS C, REFOLO MG, D’ALESSANDRO R, et al. Resistance to multikinase inhibitor actions mediated by insulin like growth factor-1[J]. J Exp Clin Cancer Res, 2015, 34:90.
    [35] REFOLO MG, D’ALESSANDRO R, LIPPOLIS C, et al. IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines[J]. Oncotarget, 2017, 8(61):103465-103476.
    [36] LIU R, LI Y, TIAN L, et al. Gankyrin drives metabolic reprogramming to promote tumorigenesis, metastasis and drug resistance through activatingβ-catenin/c-Myc signaling in human hepatocellular carcinoma[J]. Cancer Lett, 2019, 443:34-46.
    [37] MARIA R, CATIA L, NICOLA C, et al. Chlorogenic acid improves the regorafenib effects in human hepatocellular carcinoma cells[J]. Int J Mol Sci, 2018, 19(5):1518.
    [38] TERASHIMA T, YAMASHITA T, SUNAGOZAKA H, et al. Analysis of the liver functional reserve of patients with advanced hepatocellular carcinoma undergoing sorafenib treatment:Prospects for regorafenib therapy[J]. Hepatol Res, 2018, 48(12):956-966.
    [39] KUZUYA T, ISHIGAMI M, ITO T. Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment[J]. Hepatol Res, 2019,49(9):1054-1065.
    [40] OGASAWARA S, CHIBA T, OOKA Y, et al. Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment[J]. Invest New Drugs, 2018, 36(2):332-339.
    [41] UCHIKAWA S, KAWAOKA T, AIKATA H, et al. Clinical outcomes of sorafenib treatment failure for advanced hepatocel ular carcinoma and candidates for regorafenib treatment in real-world practice[J]. Hepatol Res. 2018, 48(10):814-820.
    [42] HIRAOKA A, KUMADA T, MICHITAKA K, et al. Usefulness of albuminbilirubin grade for evaluation of prognosis of 2584 Japanese patients with hepatocellular carcinoma[J]. J Gastroenterol Hepatol, 2016, 31(5):1031-1036.
    [43] PINATO DJ, YEN C, BETTINGER D, et al. The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure:Implications for drug development[J]. Aliment Pharmacol Ther, 2017, 45(5):714-722.
    [44] YUKIMOTO A, HIROOKA M, HIRAOKA A, et al. Using ALBI score at the start of sorafenib treatment to predict regorafenib treatment candidates in patients with hepatocellular carcinoma[J]. Jpn J Clin Oncol, 2019, 49(1):42-47.
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