Chemoresistance and resistance to targeted therapies in biliary tract cancer: what have we learned?

References

• Ouyang G, Liu Q, Wu Y, et al. The global, regional, and national burden of gallbladder and biliary tract cancer and its attribuTable risk factors in 195 countries and territories, 1990 to 2017: a systematic analysis for the global burden of disease study 2017. Cancer. 2021Jul 1;127(13):2238–2250.
   PubMed Web of Science ®Google Scholar
• Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273–1281.
   PubMed Web of Science ®Google Scholar
• Valle JW, Borbath I, Khan SA, et al. Biliary cancer: esmo clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v28–v37.
   PubMed Web of Science ®Google Scholar
• Valle JW, Kelley RK, Nervi B, et al. Biliary tract cancer. Lancet. 2021 Jan 30;397(10272):428–444.
   PubMed Web of Science ®Google Scholar
• Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557–588. (•) Excellent update on BTC - basic research and clinical aspects.
   PubMed Web of Science ®Google Scholar
• Marin JJG, Sanchon-Sanchez P, Cives-Losada C, et al. Novel pharmacological options in the treatment of cholangiocarcinoma: mechanisms of resistance. Cancers (Basel). 2021 May 13;13(10). 2358.
   PubMed Web of Science ®Google Scholar
• Valle JW, Furuse J, Jitlal M, et al. Cisplatin and gemcitabine for advanced biliary tract cancer: a meta-analysis of two randomised trials. Ann Oncol. 2014 Feb;25(2):391–398.
   PubMed Web of Science ®Google Scholar
• Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014 Jun;60(6):1268–1289.
   PubMed Web of Science ®Google Scholar
• Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019 Jun 1;5(6):824–830.
   PubMed Web of Science ®Google Scholar
• Phelip JM, Desrame J, Edeline J, et al. Modified FOLFIRINOX versus CISGEM as first-line chemotherapy for advanced biliary tract cancer: results of AMEBICA PRODIGE 38 randomized phase II trial. Ann Oncol. 2020 Sep;31:S260–S261.
   Web of Science ®Google Scholar
• Lamarca A, Palmer DH, Wasan HS, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690–701.
   PubMed Web of Science ®Google Scholar
• Yoo C, Jeong JH, Kim KP, et al. Multicenter randomized phase II trial of 5-fluorouracil/leucovorin (5-FU/LV) with or without liposomal irinotecan (nal-IRI) in metastatic biliary tract cancer (BTC) as second-line therapy after progression on gemcitabine plus cisplatin (gemCis): NIFTY trial. Ann Oncol. 2019 Oct;30.
   Web of Science ®Google Scholar
• Farshidfar F, Zheng S, Gingras MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct idh-mutant molecular profiles. Cell Rep. 2017 Jun 27;19(13):2878–2880.
   PubMed Web of Science ®Google Scholar
• Quaas A, Rehkaemper J, Rueschoff J, et al. Occurrence of high microsatellite-instability/mismatch repair deficiency in nearly 2,000 human adenocarcinomas of the gastrointestinal tract, pancreas, and bile ducts: a study from a large German comprehensive cancer center. Front Oncol. 2021;11:569475.
   PubMed Web of Science ®Google Scholar
• Vogel A, Bathon M, Saborowski A Immunotherapies in clinical development for biliary tract cancer. Expert Opin Investig Drugs. 2021 Apr;30(4):351–363.
   PubMed Web of Science ®Google Scholar
• Rizzo A, Ricci AD, Brandi G PD-L1, TMB, MSI, and other predictors of response to immune checkpoint inhibitors in biliary tract cancer. Cancers (Basel). 2021 Feb 1;13(3). 558
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020 May;21(5):671–684.
   PubMed Web of Science ®Google Scholar
• Mazzaferro V, El-Rayes BF, Droz Dit Busset M, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. Br J Cancer. 2019 Jan;120(2):165–171.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Macarulla T, Javle MM, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with idh1 mutation. JAMA Oncol. 2021 Sep 23. 7 11 1669
   PubMed Web of Science ®Google Scholar
• Javle M, Roychowdhury S, Kelley RK, 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. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803–815.
   PubMed Web of Science ®Google Scholar
• Goyal L, Meric-Bernstam F, Hollebecque A, et al. Primary results of phase 2 FOENIX-CCA2: the irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions/rearrangements. Cancer Res. 2021 Jul;81(13).
   Web of Science ®Google Scholar
• Park JO, Feng YH, Chen YY, et al. Updated results of a phase IIa study to evaluate the clinical efficacy and safety of erdafitinib in Asian advanced cholangiocarcinoma (CCA) patients with FGFR alterations. J Clin Oncol. 2019 May 20;37(15). 4117–4118
   Web of Science ®Google Scholar
• Subbiah V, Lassen U, Elez E, et al. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020 Sep;21(9):1234–1243.
   PubMed Web of Science ®Google Scholar
• Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021 Sep;22(9):1290–1300.
   PubMed Web of Science ®Google Scholar
• Jain A, Javle M Molecular profiling of biliary tract cancer: a target rich disease. J Gastrointest Oncol. 2016 Oct;7(5):797–803.
   PubMed Web of Science ®Google Scholar
• Marin JJG, Lozano E, Herraez E, et al. Chemoresistance and chemosensitization in cholangiocarcinoma. Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1444–1453.
   PubMed Web of Science ®Google Scholar
• Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015 Sep;47(9):1003–1010.
   PubMed Web of Science ®Google Scholar
• Marin JJG, Prete MG, Lamarca A, et al. Current and novel therapeutic opportunities for systemic therapy in biliary cancer. Br J Cancer. 2020 Sep;123(7):1047–1059.
   PubMed Web of Science ®Google Scholar
• Wang BL, Zhai HY, Chen BY, et al. Clinical relationship between MDR1 gene and gallbladder cancer. Hepatobiliary Pancreat Dis Int. 2004 May;3(2):296–299.
   PubMedGoogle Scholar
• Kreso A, Dick JE Evolution of the cancer stem cell model. Cell Stem Cell. 2014 Mar 6;14(3):275–291.
   PubMed Web of Science ®Google Scholar
• Mayr C, Ocker M, Ritter M, et al. Biliary tract cancer stem cells - translational options and challenges. World J Gastroenterol. 2017 Apr 14;23(14):2470–2482.
   PubMed Web of Science ®Google Scholar
• Agrawal S, Kuvshinoff BW, Khoury T, et al. CD24 expression is an independent prognostic marker in cholangiocarcinoma. J Gastrointest Surg. 2007 Apr;11(4):445–451.
   PubMed Web of Science ®Google Scholar
• Shuang ZY, Wu WC, Xu J, et al. Transforming growth factor-beta1-induced epithelial-mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma. Cancer Lett. 2014 Nov 28;354(2):320–328.
   PubMed Web of Science ®Google Scholar
• Chen MH, Weng JJ, Cheng CT, et al. ALDH1A3, the major aldehyde dehydrogenase isoform in human cholangiocarcinoma cells, affects prognosis and gemcitabine resistance in cholangiocarcinoma patients. Clin Cancer Res. 2016Aug 15;22(16):4225–4235.
   PubMed Web of Science ®Google Scholar
• Kalluri R, Weinberg RA The basics of epithelial-mesenchymal transition. J Clin Invest. 2009 Jun;119(6):1420–1428.
   PubMed Web of Science ®Google Scholar
• Yamada D, Kobayashi S, Wada H, et al. Role of crosstalk between interleukin-6 and transforming growth factor-beta 1 in epithelial-mesenchymal transition and chemoresistance in biliary tract cancer. Eur J Cancer. 2013 May;49(7):1725–1740.
   PubMed Web of Science ®Google Scholar
• Vaquero J, Guedj N, Claperon A, et al. Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks. J Hepatol. 2017 Feb;66(2):424–441.
   PubMed Web of Science ®Google Scholar
• Leyva-Illades D, McMillin M, Quinn M, et al. Cholangiocarcinoma pathogenesis: role of the tumor microenvironment. Transl Gastrointest Cancer. 2012;1(1):71–80.
   PubMedGoogle Scholar
• Mertens JC, Fingas CD, Christensen JD, et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 2013 Jan 15;73(2):897–907.
   PubMed Web of Science ®Google Scholar
• Carpino G, Overi D, Melandro F, et al. Matrisome analysis of intrahepatic cholangiocarcinoma unveils a peculiar cancer-associated extracellular matrix structure. Clin Proteomics. 2019;16:37. 1
   PubMed Web of Science ®Google Scholar
• Sirica AE, Almenara JA, Li C Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications. Exp Mol Pathol. 2014 Dec;97(3):515–524.
   PubMed Web of Science ®Google Scholar
• Xiao ZM, Wang XY, Wang AM Periostin induces chemoresistance in colon cancer cells through activation of the PI3K/Akt/survivin pathway. Biotechnol Appl Biochem. 2015 May-Jun;62(3):401–406.
   PubMed Web of Science ®Google Scholar
• Kajiyama K, Maeda T, Takenaka K, et al. The significance of stromal desmoplasia in intrahepatic cholangiocarcinoma: a special reference of ‘scirrhous-type’ and ‘nonscirrhous-type’ growth. Am J Surg Pathol. 1999 Aug;23(8):892–902.
   PubMed Web of Science ®Google Scholar
• Peraldo-Neia C, Massa A, Vita F, et al. A novel multidrug-resistant cell line from an Italian intrahepatic cholangiocarcinoma patient. Cancers (Basel). 2021 Apr 23;13(9). 2051
   PubMed Web of Science ®Google Scholar
• Choodetwattana P, Proungvitaya S, Jearanaikoon P, et al. The upregulation of oct4 in acidic extracellular ph is associated with gemcitabine resistance in cholangiocarcinoma cell lines. Asian Pac J Cancer Prev. 019 Sep 1;20(9):2745–2748.
   PubMedGoogle Scholar
• Ruiz-Vela A, Aguilar-Gallardo C, Simon C Building a framework for embryonic microenvironments and cancer stem cells. Stem Cell Rev Rep. 2009 Dec;5(4):319–327.
   PubMed Web of Science ®Google Scholar
• Shi CJ, Gao J, Wang M, et al. CD133(+) gallbladder carcinoma cells exhibit self-renewal ability and tumorigenicity. World J Gastroenterol. 2011 Jun 28;17(24):2965–2971.
   PubMed Web of Science ®Google Scholar
• Hasita H, Komohara Y, Okabe H, et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010 Aug;101(8):1913–1919.
   PubMed Web of Science ®Google Scholar
• Subimerb C, Pinlaor S, Khuntikeo N, et al. Tissue invasive macrophage density is correlated with prognosis in cholangiocarcinoma. Mol Med Rep. 2010 Jul-Aug;3(4):597–605.
   PubMed Web of Science ®Google Scholar
• Ghidini M, Cascione L, Carotenuto P, et al. Characterisation of the immune-related transcriptome in resected biliary tract cancers. Eur J Cancer. 2017 Nov;86:158–165.
   PubMed Web of Science ®Google Scholar
• Mayr C, Beyreis M, Wagner A, et al. Deregulated micrornas in biliary tract cancer: functional targets and potential biomarkers. Biomed Res Int. 2016;2016:4805270.
   PubMed Web of Science ®Google Scholar
• Bartel DP MicroRNAs: target recognition and regulatory functions. Cell. 2009 Jan 23;136(2):215–233.
   PubMed Web of Science ®Google Scholar
• Zhan M, Zhao X, Wang H, et al. miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1. Tumour Biol. 2016 Aug;37(8):10553–10562.
   PubMedGoogle Scholar
• Okamoto K, Miyoshi K, Murawaki Y miR-29b, miR-205 and miR-221 enhance chemosensitivity to gemcitabine in HuH28 human cholangiocarcinoma cells. PLoS One. 2013;8(10):e77623.
   PubMed Web of Science ®Google Scholar
• Khandelwal A, Bacolla A, Vasquez KM, et al. Long non-coding RNA: a new paradigm for lung cancer. Mol Carcinog. 2015 Nov;54(11):1235–1251.
   PubMed Web of Science ®Google Scholar
• Bekric D, Neureiter D, Ritter M, et al. Long non-coding RNAs in biliary tract cancer-an up-to-date review. J Clin Med. 2020 Apr 22;9(4). 1200
   Web of Science ®Google Scholar
• Cai Q, Wang S, Jin L, et al. Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy. Mol Cancer. 2019 Apr 5;18(1):82.
   PubMedGoogle Scholar
• Parasramka M, Yan IK, Wang X, et al. BAP1 dependent expression of long non-coding RNA NEAT-1 contributes to sensitivity to gemcitabine in cholangiocarcinoma. Mol Cancer. 2017 Jan 25;16(1):22.
   PubMedGoogle Scholar
• Marin JJG, Lozano E, Briz O, et al. Molecular bases of chemoresistance in cholangiocarcinoma. Curr Drug Targets. 2017;18(8):889–900.
   PubMed Web of Science ®Google Scholar
• Fouassier L, Marzioni M, Afonso MB, et al. Signalling networks in cholangiocarcinoma: molecular pathogenesis, targeted therapies and drug resistance. Liver Int. 2019 May;39 Suppl 1:43–62.
   PubMedGoogle Scholar
• Marin JJG, Macias RIR, Monte MJ, et al. Molecular bases of drug resistance in hepatocellular carcinoma. Cancers (Basel). 2020 Jun 23;12(6).
   Web of Science ®Google Scholar
• Pastor-Anglada M, Molina-Arcas M, Casado FJ, et al. Nucleoside transporters in chronic lymphocytic leukaemia. Leukemia. 2004 Mar;18(3):385–393.
   PubMed Web of Science ®Google Scholar
• Borbath I, Verbrugghe L, Lai R, et al. Human equilibrative nucleoside transporter 1 (hENT1) expression is a potential predictive tool for response to gemcitabine in patients with advanced cholangiocarcinoma. Eur J Cancer. 2012 May;48(7):990–996.
   PubMed Web of Science ®Google Scholar
• Martinez-Becerra P, Vaquero J, Romero MR, et al. No correlation between the expression of FXR and genes involved in multidrug resistance phenotype of primary liver tumors. Mol Pharm. 2012 Jun 4;9(6):1693–1704.
   PubMedGoogle Scholar
• Tepsiri N, Chaturat L, Sripa B, et al. Drug sensitivity and drug resistance profiles of human intrahepatic cholangiocarcinoma cell lines. World J Gastroenterol. 2005 May 14;11(18):2748–2753.
   PubMed Web of Science ®Google Scholar
• Cao L, Duchrow M, Windhovel U, et al. Expression of MDR1 mRNA and encoding P-glycoprotein in archival formalin-fixed paraffin-embedded gall bladder cancer tissues. Eur J Cancer. 1998 Sep;34(10):1612–1617.
   PubMed Web of Science ®Google Scholar
• Srimunta U, Sawanyawisuth K, Kraiklang R, et al. High expression of ABCC1 indicates poor prognosis in intrahepatic cholangiocarcinoma. Asian Pac J Cancer Prev. 2012;13 Suppl: 125–130.
   PubMed Web of Science ®Google Scholar
• Yang J, Sontag D, Gong Y, et al. Enhanced gemcitabine cytotoxicity with knockdown of multidrug resistance protein genes in human cholangiocarcinoma cell lines. J Gastroenterol Hepatol. 2021 Apr;36(4):1103–1109.
   PubMed Web of Science ®Google Scholar
• Hahnvajanawong C, Chaiyagool J, Seubwai W, et al. Orotate phosphoribosyl transferase mRNA expression and the response of cholangiocarcinoma to 5-fluorouracil. World J Gastroenterol. 2012 Aug 14;18(30):3955–3961.
   PubMed Web of Science ®Google Scholar
• Schmitz KJ, Lang H, Kaiser G, et al. Metallothionein overexpression and its prognostic relevance in intrahepatic cholangiocarcinoma and extrahepatic hilar cholangiocarcinoma (Klatskin tumors). Hum Pathol. 2009 Dec;40(12):1706–1714.
   PubMed Web of Science ®Google Scholar
• Srijiwangsa P, Ponnikorn S, Na-Bangchang K Effect of beta-Eudesmol on NQO1 suppression-enhanced sensitivity of cholangiocarcinoma cells to chemotherapeutic agents. BMC Pharmacol Toxicol.2018 Jun 19;19(1):32.
   PubMedGoogle Scholar
• Sato J, Kimura T, Saito T, et al. Gene expression analysis for predicting gemcitabine resistance in human cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 2011 Sep;18(5):700–711.
   PubMed Web of Science ®Google Scholar
• Fisher SB, Fisher KE, Patel SH, et al. Excision repair cross-complementing gene-1, ribonucleotide reductase subunit M1, ribonucleotide reductase subunit M2, and human equilibrative nucleoside transporter-1 expression and prognostic value in biliary tract malignancy. Cancer. 2013 Jan 15;119(2):454–462.
   PubMed Web of Science ®Google Scholar
• Hwang IG, Jang JS, Do JH, et al. Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients. Cancer Chemother Pharmacol. 2011 Oct;68(4):935–944.
   PubMed Web of Science ®Google Scholar
• Ge X, Wang Y, Li Q, et al. NK4 regulates 5-fluorouracil sensitivity in cholangiocarcinoma cells by modulating the intrinsic apoptosis pathway. Oncol Rep. 2013 Jul;30(1):448–454.
   PubMed Web of Science ®Google Scholar
• Wattanawongdon W, Hahnvajanawong C, Namwat N, et al. Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness. Int J Oncol. 2015 Jul;47(1):398–410.
   PubMed Web of Science ®Google Scholar
• Marin JJG, Briz O, Herraez E, et al. Molecular bases of the poor response of liver cancer to chemotherapy. Clin Res Hepatol Gastroenterol. 2018 Jun;42(3):182–192.
   PubMed Web of Science ®Google Scholar
• Morton SD, Cadamuro M, Brivio S, et al. Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation. Oncotarget. 2015 Sep 22;6(28):26052–26064.
   PubMedGoogle Scholar
• Quintavalle C, Burmeister K, Piscuoglio S, et al. High mobility group A1 enhances tumorigenicity of human cholangiocarcinoma and confers resistance to therapy. Mol Carcinog. 2017 Sep;56(9):2146–2157.
   PubMed Web of Science ®Google Scholar
• Sirica AE, Gores GJ Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting. Hepatology. 2014 Jun;59(6):2397–2402.
   PubMed Web of Science ®Google Scholar
• Herraez E, Lozano E, Macias RI, et al. Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib. Hepatology. 2013 Sep;58(3):1065–1073.
   PubMed Web of Science ®Google Scholar
• Lozano E, Macias RIR, Monte MJ, et al. Causes of hOCT1-dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor-selective gene therapy. Hepatology. 2019 Oct;70(4):1246–1261.
   PubMed Web of Science ®Google Scholar
• Marin JJ, Romero MR, Briz O Molecular bases of liver cancer refractoriness to pharmacological treatment. Curr Med Chem. 2010;17(8):709–740.
   PubMed Web of Science ®Google Scholar
• Peraldo-Neia C, Cavalloni G, Fenocchio E, et al. Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR. PLoS One. 2018;13(1):e0191593.
   PubMed Web of Science ®Google Scholar
• Hezel AF, Deshpande V, Zhu AX Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010 Jul 20;28(21):3531–3540.
   PubMed Web of Science ®Google Scholar
• Cavalloni G, Peraldo-Neia C, Varamo C, et al. Preclinical activity of EGFR and MEK1/2 inhibitors in the treatment of biliary tract carcinoma. Oncotarget. 2016 Aug 9;7(32):52354–52363.
   PubMedGoogle Scholar
• Vaquero J, Lobe C, Tahraoui S, et al. The IGF2/IR/igf1r pathway in tumor cells and myofibroblasts mediates resistance to egfr inhibition in cholangiocarcinoma. Clin Cancer Res. 2018 Sep 1;24(17):4282–4296.
   PubMed Web of Science ®Google Scholar
• Goyal L, Saha SK, Liu LY, et al. Polyclonal secondary fgfr2 mutations drive acquired resistance to fgfr inhibition in patients with fgfr2 fusion-positive cholangiocarcinoma. Cancer Discov. 2017 Mar;7(3):252–263.
   PubMed Web of Science ®Google Scholar
• Goyal L, Liu LY, Lennerz JK, et al. NTAS120, a covalently-binding FGFR inhibitor (FGFRi), overcomes resistance to BGJ398 in patients with FGFR2 fusion positive cholangiocarcinoma. Cancer Res. 2018 Jul;78(13).
   Web of Science ®Google Scholar
• Lamberti D, Cristinziano G, Porru M, et al. HSP90 inhibition drives degradation of fgfr2 fusion proteins: implications for treatment of cholangiocarcinoma. Hepatology. 2019 Jan;69(1):131–142.
   PubMed Web of Science ®Google Scholar
• Yokoi K, Kobayashi A, Motoyama H, et al. Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib. Oncol Rep. 2018 Feb;39(2):843–850.
   PubMed Web of Science ®Google Scholar
• Wu S, Fu L Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells. Mol Cancer. 2018 Feb 19;17(1):25.
   PubMedGoogle Scholar
• Geier A, Macias RI, Bettinger D, et al. The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma. Oncotarget. 2017 Feb 28;8(9):15846–15857.
   PubMedGoogle Scholar
• Grimm D, Lieb J, Weyer V, et al. Organic cation transporter 1 (OCT1) mRNA expression in hepatocellular carcinoma as a biomarker for sorafenib treatment. BMC Cancer. 2016 Feb 12;16:94. 1
   PubMedGoogle Scholar
• Lozano E, Herraez E, Briz O, et al. Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. Biomed Res Int. 2013; 2013:692071. 2013
   PubMed Web of Science ®Google Scholar
• Cirqueira CS, Felipe-Silva AS, Wakamatsu A, et al. Immunohistochemical assessment of the expression of biliary transportation proteins mrp2 and mrp3 in hepatocellular carcinoma and in cholangiocarcinoma. Pathol Oncol Res. 2019 Oct;25(4):1363–1371.
   PubMed Web of Science ®Google Scholar
• Briz O, Serrano MA, Rebollo N, et al. Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis-diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells. Mol Pharmacol. 2002 Apr;61(4):853–860.
   PubMed Web of Science ®Google Scholar
• Lozano E, Asensio M, Perez-Silva L, et al. MRP3-Mediated chemoresistance in cholangiocarcinoma: target for chemosensitization through restoring sox17 expression. Hepatology. 2020 Sep;72(3):949–964.
   PubMed Web of Science ®Google Scholar
• Herraez E, Sanchez-Vicente L, Macias RIR, et al. Usefulness of the MRP2 promoter to overcome the chemoresistance of gastrointestinal and liver tumors by enhancing the expression of the drug transporter OATP1B1. Oncotarget. 2017 May 23;8(21):34617–34629.
   PubMedGoogle Scholar
• Wang C, Ye H, Zhang L, et al. Enhanced expression of ten-eleven translocation 1 reverses gemcitabine resistance in cholangiocarcinoma accompanied by a reduction in P-glycoprotein expression. Cancer Med. 2019 Mar;8(3):990–1003.
   PubMed Web of Science ®Google Scholar
• Zhan M, Wang H, Xu S-W, et al. Variants in oxidative stress-related genes affect the chemosensitivity through Nrf2-mediated signaling pathway in biliary tract cancer. EBioMedicine. 2019 Oct;48:143–160.
   PubMed Web of Science ®Google Scholar
• Yu J, Shi L, Lin W, et al. UCP2 promotes proliferation and chemoresistance through regulating the NF-kappaB/beta-catenin axis and mitochondrial ROS in gallbladder cancer. Biochem Pharmacol. 2020 Feb;172:113745.
   PubMed Web of Science ®Google Scholar
• Carotenuto P, Hedayat S, Fassan M, et al. Modulation of biliary cancer chemo-resistance through microRNA-mediated rewiring of the expansion of cd133+ Cells. Hepatology. 2020 Sep;72(3):982–996.
   PubMed Web of Science ®Google Scholar
• Chen L, Yan HX, Yang W, et al. The role of microRNA expression pattern in human intrahepatic cholangiocarcinoma. J Hepatol. 2009 Feb;50(2):358–369.
   PubMed Web of Science ®Google Scholar
• Meng F, Henson R, Lang M, et al. Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology. 2006 Jun;130(7):2113–2129.
   PubMed Web of Science ®Google Scholar
• Salati M, Braconi C Noncoding RNA in cholangiocarcinoma. Semin Liver Dis. 2019 Feb;39(1):13–25.
   PubMed Web of Science ®Google Scholar
• Zhang KP, Fang X, Zhang Y, et al. The prognosis of cancer patients undergoing liposomal doxorubicin-based chemotherapy: a systematic review and meta-analysis. Medicine (Baltimore). 2021 Aug 27;100(34):e26690.
   PubMed Web of Science ®Google Scholar
• Rezvantalab S, Drude NI, Moraveji MK, et al. PLGA-based nanoparticles in cancer treatment. Front Pharmacol. 2018;9:1260.
   PubMed Web of Science ®Google Scholar
• Wu HJ, Chu PY Role of cancer stem cells in cholangiocarcinoma and therapeutic implications. Int J Mol Sci. 2019 Aug 25;20(17). 4154
   Web of Science ®Google Scholar
• Galadari S, Rahman A, Pallichankandy S, et al. Reactive oxygen species and cancer paradox: to promote or to suppress? Free Radic Biol Med. 2017 Mar;104:144–164.
   PubMed Web of Science ®Google Scholar
• Ikeda M, Ohno I, Ueno H, et al. Phase I study of resminostat, an HDAC inhibitor, combined with S-1 in patients with pre-treated biliary tract or pancreatic cancer. Invest New Drugs. 2019 Feb;37(1):109–117.
   PubMed Web of Science ®Google Scholar
• Mayr C, Helm K, Jakab M, et al. The histone methyltransferase G9a: a new therapeutic target in biliary tract cancer. Hum Pathol. 2018 Feb;72:117–126.
   PubMed Web of Science ®Google Scholar
• Mayr C, Kiesslich T, Erber S, et al. HDAC screening identifies the HDAC class I inhibitor romidepsin as a promising epigenetic drug for biliary tract cancer. Cancers (Basel). 2021 Jul 31;13(15). 3862
   PubMed Web of Science ®Google Scholar
• Garcia-Costela M, Escudero-Feliu J, Puentes-Pardo JD, et al. Circadian genes as therapeutic targets in pancreatic cancer. Front Endocrinol (Lausanne). 2020;11:638.
   PubMed Web of Science ®Google Scholar
• Kiesslich T, Mayr C, Neureiter D NRF2: the key to tumor- and patient-dependent chemosensitivity in biliary tract cancer? EBioMedicine. 2019 Nov;49:9–10.
   PubMed Web of Science ®Google Scholar
• Schmidlin CJ, Shakya A, Dodson M, et al. The intricacies of NRF2 regulation in cancer. Semin Cancer Biol. 2021 May 18. 76 110–119
   PubMed Web of Science ®Google Scholar
• Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018 Feb 23;359(6378):920–926.
   PubMed Web of Science ®Google Scholar
• Amato F, Rae C, Prete MG, et al. Cholangiocarcinoma disease modelling through patients derived organoids. Cells. 2020 Mar 30;9(4). 832
   Web of Science ®Google Scholar
• Hummel R, Hussey DJ, Haier J MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer. 2010 Jan;46(2):298–311.
   PubMed Web of Science ®Google Scholar
• Lozano E, Monte MJ, Briz O, et al. Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT). J Control Release. 2015 Oct 28;216:93–102.
   PubMed Web of Science ®Google Scholar
• Lie ALM, Bakker CT, Deurholt T, et al. Selection of tumour specific promoters for adenoviral gene therapy of cholangiocarcinoma. J Hepatol. 2006 Jan;44(1):126–133.
   PubMed Web of Science ®Google Scholar
• Nagi P, Vickers SM, Davydova J, et al. Development of a therapeutic adenoviral vector for cholangiocarcinoma combining tumor-restricted gene expression and infectivity enhancement. J Gastrointest Surg. 2003 Mar-Apr;7(3):364–371.
   PubMed Web of Science ®Google Scholar