Emerging Molecular Therapeutic Targets for Cholangiocarcinoma

J Hepatol. 2017 Sep;67(3):632-644. doi: 10.1016/j.jhep.2017.03.026. Epub 2017 Apr 5.


Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation. CCAs are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early-stage disease. Presently, the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy. Molecular alterations define the differences in biological behavior of each CCA subtype. Recent comprehensive genetic analysis has better characterized the genomic and transcriptomic landscape of each CCA subtype. Promising candidates for targeted, personalized therapy have emerged, including potential driver fibroblast growth factor receptor (FGFR) gene fusions and somatic mutations in isocitrate dehydrogenase (IDH)1/2 in iCCA, protein kinase cAMP-activated catalytic subunit alpha (PRKACA) or beta (PRKACB) gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma. A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers. We review the current genomic landscape of CCA, the potentially actionable molecular aberrations in each CCA subtype, and the role of immunotherapy in CCA.

Keywords: Distal cholangiocarcinoma; Immunotherapy; Intrahepatic cholangiocarcinoma; Perihilar cholangiocarcinoma; Targeted therapy.

Publication types

  • Review

MeSH terms

  • Bile Duct Neoplasms / drug therapy*
  • Bile Duct Neoplasms / genetics
  • Bile Duct Neoplasms / mortality
  • Cholangiocarcinoma / drug therapy*
  • Cholangiocarcinoma / genetics
  • Cholangiocarcinoma / mortality
  • Hepatocyte Growth Factor / antagonists & inhibitors
  • Histone Deacetylase Inhibitors / therapeutic use
  • Humans
  • Immunotherapy
  • Isocitrate Dehydrogenase / antagonists & inhibitors
  • Molecular Targeted Therapy*
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors


  • Histone Deacetylase Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Fibroblast Growth Factor
  • Hepatocyte Growth Factor
  • Isocitrate Dehydrogenase
  • Proto-Oncogene Proteins c-met