肝内胆管癌驱动基因改变及靶向治疗的研究进展

摘要/Abstract

摘要： 肝内胆管癌（intrahepatic cholangiocarcinoma,ICCA）是起源于肝内胆管上皮的肝脏原发性恶性肿瘤,发病率仅次于肝细胞癌,恶性程度极高,5年总生存率不足10%。手术治疗是其首选的治疗方法,晚期ICCA患者放化疗抵抗,治疗效果不理想,亟需寻找新的有效的治疗方法。随着精准医疗时代的到来,近年来国内外对于ICCA多种驱动基因改变及信号通路异常的机制研究不断深入,靶向治疗和免疫治疗探索已越来越广泛地应用于临床实践。本文拟对ICCA驱动基因改变及靶向治疗的研究进展进行综述。

关键词: 肝内胆管癌, 驱动基因, 靶向治疗

Abstract: Intrahepatic cholangiocarcinoma (ICCA) is a primary liver cancer originating from the intrahepatic bile duct epithelium, which is second only to hepatocellular carcinoma in terms of incidence and is extremely malignant with a 5-year overall survival rate of less than 10%. Surgery is the perferred radical treatment choice. Patients with advanced disease are resistant to radiotherapy or chemotherapy, the efficacy is unsatisfactory, and there is an urgent need to find new and effective treatment methods. With the advent of precision medicine, research on the mechanisms of multiple driver gene alterations and signaling pathway abnormalities in intrahepatic cholangiocarcinoma in China and abroad has been intensifying in recent years, and targeted therapy and immunotherapy have been more and more widely used in clinical practice. This paper is intended to review the research progress of driver gene alterations and targeted therapies for intrahepatic cholangiocarcinoma.

Key words: Intrahepatic cholangiocarcinoma, Driver genes, Targeted therapies

张诗汇, 李卓, 依荷芭丽·迟, 石素胜. 肝内胆管癌驱动基因改变及靶向治疗的研究进展[J]. 肝癌电子杂志, 2023, 10(4): 15-22.

Zhang Shihui, Li Zhuo, Yihebali·Chi, Shi Susheng. Research progress of driver gene alteration and targeted therapy for intrahepatic cholangiocarcinoma[J]. Electronic Journal of Liver Tumor, 2023, 10(4): 15-22.

参考文献

[1] BANALES J M, CARDINALE V, CARPINO G, et al.Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)[J]. Nat Rev Gastroenterol Hepatol, 2016, 13(5): 261-280.
[2] BANALES J M, MARIN J J G, LAMARCA A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(9): 557-588.
[3] LENDVAI G, SZEKERCZÉS T, ILLYÉS I, et al. Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis[J]. Pathol Oncol Res, 2020, 26(1): 3-15.
[4] SUH K S, ROH H R, KOH Y T, et al.Clinicopathologic features of the intraductal growth type of peripheral cholangiocarcinoma[J]. Hepatology, 2000, 31(1): 12-17.
[5] VIJGEN S, TERRIS B, RUBBIA-BRANDT L.Pathology of intrahepatic cholangiocarcinoma[J]. Hepatobiliary Surg Nutr, 2017, 6(1): 22-34.
[6] KOMUTA M.Intrahepatic cholangiocarcinoma: Tumour heterogeneity and its clinical relevance[J]. Clin Mol Hepatol, 2022, 28(3): 396-407.
[7] LIAU J Y, TSAI J H, YUAN R H, et al.Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features[J]. Mod Pathol, 2014, 27(8): 1163-1173.
[8] DONG L Q, PENG L H, MA L J, et al.Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma[J]. J Hepatol, 2020, 72(5): 896-908.
[9] SIA D, HOSHIDA Y, VILLANUEVA A, et al.Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes[J]. Gastroenterology, 2013, 144(4): 829-840.
[10] RHEE H, KO J E, CHUNG T, et al.Transcriptomic and histopathological analysis of cholangiolocellular differentiation trait in intrahepatic cholangiocarcinoma[J]. Liver Int, 2018, 38(1): 113-124.
[11] WANG X Y, ZHU W W, WANG Z, et al.Driver mutations of intrahepatic cholangiocarcinoma shape clinically relevant genomic clusters with distinct molecular features and therapeutic vulnerabilities[J]. Theranostics, 2022, 12(1): 260-276.
[12] XU S, GUO Y, ZENG Y, et al.Clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma[J]. BMC Cancer, 2021, 21(1): 152.
[13] WANG L, ZHU H, ZHAO Y, et al.Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience[J]. J Transl Med, 2020, 18(1): 273.
[14] PU X, ZHU L, LI F, et al.Target molecular treatment markers in Intrahepatic Cholangiocarcinoma based on Chinese population[J]. Pathol Res Pract, 2020, 216(9): 153116.
[15] MIAO X, HU J, CHAI C, et al.Establishment and characterization of a new intrahepatic cholangiocarcinoma cell line derived from a Chinese patient[J]. Cancer Cell Int, 2022, 22(1): 418.
[16] CAIRNS R A, MAK T W.Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities[J]. Cancer Discov, 2013, 3(7): 730-741.
[17] BOSCOE A N, ROLLAND C, KELLEY R K.Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review[J]. J Gastrointest Oncol, 2019, 10(4): 751-765.
[18] MONDESIR J, WILLEKENS C, TOUAT M, et al.IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives[J]. J Blood Med, 2016, 7: 171-180.
[19] XU X, ZHAO J, XU Z, et al.Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity[J]. J Biol Chem, 2004, 279(32): 33946-33957.
[20] CRISPO F, PIETRAFESA M, CONDELLI V, et al.IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment-Current State and Future Perspectives[J]. Molecules, 2020, 25(16): 3754.
[21] DANG L, WHITE DW, GROSS S, et al.Cancer-associated IDH1 mutations produce 2-hydroxyglutarate[J]. Nature, 2009, 462(7274): 739-744.
[22] SCIACOVELLI M, FREZZA C.Oncometabolites: Unconventional triggers of oncogenic signalling cascades[J]. Free Radic Biol Med, 2016, 100: 175-181.
[23] TOMMASINI-GHELFI S, MURNAN K, KOURI F M, et al. Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease[J]. Sci Adv, 2019, 5(5): eaaw4543.
[24] CAREY B W, FINLEY L W, CROSS J R, et al.Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells[J]. Nature, 2015, 518(7539): 413-416.
[25] LU H, DALGARD C L, MOHYELDIN A, et al.Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1[J]. J Biol Chem, 2005, 280(51): 41928-41939.
[26] JIANG L, SHESTOV A A, SWAIN P, et al.Reductive carboxylation supports redox homeostasis during anchorage-independent growth[J]. Nature, 2016, 532(7598): 255-258.
[27] ICARD P, POULAIN L, LINCET H.Understanding the central role of citrate in the metabolism of cancer cells[J]. Biochim Biophys Acta, 2012, 1825(1): 111-116.
[28] KATOH M.Fibroblast growth factor receptors as treatment targets in clinical oncology[J]. Nat Rev Clin Oncol, 2019, 16(2): 105-122.
[29] LEMMON M A, SCHLESSINGER J.Cell signaling by receptor tyrosine kinases[J]. Cell, 2010, 141(7): 1117-1134.
[30] KATOH M, NAKAGAMA H.FGF receptors: cancer biology and therapeutics[J]. Med Res Rev, 2014, 34(2): 280-300.
[31] ORNITZ D M, ITOH N.The Fibroblast Growth Factor signaling pathway[J]. Wiley Interdiscip Rev Dev Biol, 2015, 4(3): 215-266.
[32] CHEN H, MARSIGLIA W M, CHO M K, et al.Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases[J]. Elife, 2017, 6: e21137.
[33] XIE Y, SU N, YANG J, et al.FGF/FGFR signaling in health and disease[J]. Signal Transduct Target Ther, 2020, 5(1): 181.
[34] NEUMANN O, BURN T C, ALLGÄUER M, et al. Genomic architecture of FGFR2 fusions in cholangiocarcinoma and its implication for molecular testing[J]. Br J Cancer, 2022, 127(8): 1540-1549.
[35] CHA J Y, MADDILETI S, MITIN N, et al.Aberrant receptor internalization and enhanced FRS2-dependent signaling contribute to the transforming activity of the fibroblast growth factor receptor 2 Ⅲb C3 isoform[J]. J Biol Chem, 2009, 284(10): 6227-6240.
[36] CHA J Y, LAMBERT Q T, REUTHER G W, et al.Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis[J]. Mol Cancer Res, 2008, 6(3): 435-445.
[37] BELOV A A, MOHAMMADI M.Grb2, a double-edged sword of receptor tyrosine kinase signaling[J]. Sci Signal, 2012, 5(249): pe49.
[38] LIN C C, MELO F A, GHOSH R, et al.Inhibition of basal FGF receptor signaling by dimeric Grb2[J]. Cell, 2012, 149(7): 1514-1524.
[39] LI F, PEIRIS M N, DONOGHUE D J.Functions of FGFR2 corrupted by translocations in intrahepatic cholangiocarcinoma[J]. Cytokine Growth Factor Rev, 2020, 52: 56-67.
[40] ABOU-ALFA G K, SAHAI V, HOLLEBECQUE A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study[J]. Lancet Oncol, 2020, 21(5): 671-684.
[41] DUTT A, SALVESEN H B, CHEN T H, et al.Drug-sensitive FGFR2 mutations in endometrial carcinoma[J]. Proc Natl Acad Sci U S A, 2008, 105(25): 8713-8717.
[42] WANG Y, DING X, WANG S, et al.Antitumor effect of FGFR inhibitors on a novel cholangiocarcinoma patient derived xenograft mouse model endogenously expressing an FGFR2-CCDC6 fusion protein[J]. Cancer Lett, 2016, 380(1): 163-173.
[43] TSUJIE M, IWAI T, KUBO S, et al.Fibroblast growth factor receptor 2 (FGFR2) fusions in Japanese patients with intrahepatic cholangiocarcinoma[J]. Jpn J Clin Oncol, 2021, 51(6): 911-917.
[44] GUO C, LIU Z, YU Y, et al.TP53 /KRAS Co-Mutations Create Divergent Prognosis Signatures in Intrahepatic Cholangiocarcinoma[J]. Front Genet, 2022, 13: 844800.
[45] KENDRE G, MURUGESAN K, BRUMMER T, et al. Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma[J]. J Hepatol, 2022: S0168-8278(22)03328-1.
[46] GAO Z, CHEN J F, LI X G, et al.KRAS acting through ERK signaling stabilizes PD-L1 via inhibiting autophagy pathway in intrahepatic cholangiocarcinoma[J]. Cancer Cell Int, 2022, 22(1): 128.
[47] YI M, NIU M, XU L, et al.Regulation of PD-L1 expression in the tumor microenvironment[J]. J Hematol Oncol, 2021, 14(1): 10.
[48] MARCUS R, FERRI-BORGOGNO S, HOSEIN A, et al.Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma[J]. Cancers (Basel), 2021, 13(22): 5709.
[49] IKENOUE T, TERAKADO Y, NAKAGAWA H, et al.A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion[J]. Sci Rep, 2016, 6: 23899.
[50] COLYN L, ALVAREZ-SOLA G, LATASA MU, et al.New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming[J]. J Exp Clin Cancer Res, 2022, 41(1): 183.
[51] ZOU S, LI J, ZHOU H, FRECH C, et al.Mutational landscape of intrahepatic cholangiocarcinoma[J]. Nat Commun, 2014, 5: 5696.
[52] DONG L, LU D, CHEN R, et al. Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma[J]. Cancer Cell, 2022, 40(1): 70-87.e15.
[53] CARBONE M, YANG H, PASS H I, et al.BAP1 and cancer[J]. Nat Rev Cancer, 2013, 13(3): 153-159.
[54] ZHANG Y, SHI J, LIU X, et al.BAP1 links metabolic regulation of ferroptosis to tumour suppression[J]. Nat Cell Biol, 2018, 20(10): 1181-1192.
[55] BONONI A, GIORGI C, PATERGNANI S, et al.BAP1 regulates IP3R3-mediated Ca²+ flux to mitochondria suppressing cell transformation[J]. Nature, 2017, 546(7659): 549-553.
[56] NAGL NG JR, PATSIALOU A, HAINES D S, et al.The p270 (ARID1A/SMARCF1) subunit of mammalian SWI/SNF-related complexes is essential for normal cell cycle arrest[J]. Cancer Res, 2005, 65(20): 9236-9244.
[57] YANG S Z, WANG A Q, DU J, et al.Low expression of ARID1A correlates with poor prognosis in intrahepatic cholangiocarcinoma[J]. World J Gastroenterol, 2016, 22(25): 5814-5821.
[58] TESSIRI S, TECHASEN A, KONGPETCH S, et al.Therapeutic targeting of ARID1A and PI3K/AKT pathway alterations in cholangiocarcinoma[J]. PeerJ, 2022, 10: e12750.
[59] JACOBI O, ROSS J S, GOSHEN-LAGO T, et al.ERBB2 Pathway in Biliary Tract Carcinoma: Clinical Implications of a Targetable Pathway[J]. Oncol Res Treat, 2021, 44(1-2): 20-27.
[60] XIAO P, MENG Q, LIU Q, et al.IGF2BP1-mediated N6-methyladenosine modification promotes intrahepatic cholangiocarcinoma progression[J]. Cancer Lett, 2023, 557: 216075.
[61] SONG F, CHEN F Y, WU S Y, et al.Mucin 1 promotes tumor progression through activating WNT/β-catenin signaling pathway in intrahepatic cholangiocarcinoma[J]. J Cancer, 2021, 12(23): 6937-6947.
[62] ZHOU Q, WANG Y, PENG B, et al.The roles of Notch1 expression in the migration of intrahepatic cholangiocarcinoma[J]. BMC Cancer, 2013, 13: 244.
[63] WISHART D S, FEUNANG Y D, GUO A C, et al.DrugBank 5.0: a major update to the DrugBank database for 2018[J]. Nucleic Acids Res, 2018, 46(D1): D1074-D1082.
[64] ANGELAKAS A, LAMARCA A, HUBNER R A, et al.Ivosidenib: an investigational drug for the treatment of biliary tract cancers[J]. Expert Opin Investig Drugs, 2021, 30(4): 301-307.
[65] ABOU-ALFA G K, MACARULLA T, JAVLE M M, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study[J]. Lancet Oncol, 2020, 21(6): 796-807.
[66] CRISCUOLO D, AVOLIO R, CALICE G, et al.Cholesterol Homeostasis Modulates Platinum Sensitivity in Human Ovarian Cancer[J]. Cells, 2020, 9(4): 828.
[67] FAN B, MELLINGHOFF I K, WEN P Y, et al.Clinical pharmacokinetics and pharmacodynamics of ivosidenib, an oral, targeted inhibitor of mutant IDH1, in patients with advanced solid tumors[J]. Invest New Drugs, 2020, 38(2): 433-444.
[68] JAVLE M, ROYCHOWDHURY S, KELLEY R K, et al.Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study[J]. Lancet Gastroenterol Hepatol, 2021, 6(10): 803-815.
[69] MERIC-BERNSTAM F, BAHLEDA R, HIERRO C, et al.Futibatinib, an Irreversible FGFR1-4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A PhaseⅠDose-Expansion Study[J]. Cancer Discov, 2022, 12(2): 402-415.
[70] SHI G M, HUANG X Y, WEN T F, et al.Pemigatinib in previously treated Chinese patients with locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusions or rearrangements: A phase Ⅱ study[J]. Cancer Med, 2023, 12(4): 4137-4146.
[71] Zhu C, Xue J, Wang Y, et al.Efficacy and safety of lenvatinib combined with PD-1/PD-L1 inhibitors plus Gemox chemotherapy in advanced biliary tract cancer[J]. Front Immunol, 2023, 14: 1109292.
[72] LEE C K, CHON H J, CHEON J, et al.Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14)[J]. Lancet Gastroenterol Hepatol, 2023, 8(1): 56-65.
[73] CHEN R, ZHANG Y, LIN K, et al.Cost-Effectiveness Analysis of Capecitabine Plus Oxaliplatin Versus Gemcitabine Plus Oxaliplatin as First-Line Therapy for Advanced Biliary Tract Cancers[J]. Front Pharmacol, 2022, 13: 871262.
[74] SERRA-CAMPRUBÍ Q, VERDAGUER H, OLIVEROS W, et al.Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation[J]. Clin Cancer Res, 2023, 29(2): 432-445.
[75] ZHOU J, SUN Y, ZHANG W, et al.PhaseⅠb study of anlotinib combined with TQB2450 in pretreated advanced biliary tract cancer and biomarker analysis[J]. Hepatology, 2023, 77(1): 65-76.
[76] VAQUERO J, KEITEL V.Deciphering FAK in intrahepatic cholangiocarcinoma: A novel therapeutic target?[J]. J Hepatol, 2021, 75(4): 765-767.