Abstract
Cholangiocarcinoma (CCA) is a disease with a very poor prognosis and limited treatment options. Although targeted therapies directed towards specific mutations found in CCA are becoming available and are showing great potential, many tumors do not carry actionable mutations and, in those that do, the emergence of drug resistance is a likely consequence of treatment. Therapeutic targeting of enzymes and other proteins that show elevated activity in CCA cells but which are not altered by mutation is a potential strategy for the treatment of target negative and drug-resistant disease. Protein kinase CK2 (CK2) is a ubiquitously expressed kinase that has increased expression and increased activity in a variety of cancer types including CCA. Several potent CK2 inhibitors are in pre-clinical development or under assessment in a variety of clinical trials often in combination with drugs that induce DNA damage. This review outlines the importance of CK2 in CCA and assesses the progress that has been made in the evaluation of CK2 inhibition as a treatment strategy in this disease. Targeting CK2 based on the expression levels or activity of this protein and/or in combination with drugs that induce DNA damage or inhibit cell cycle progression, could be a viable option for tumors that lack actionable mutations, or for tumors that develop resistance to targeted treatments.
Highlights
Cholangiocarcinoma (CCA) is a disease with a very poor prognosis and limited treatment options
Genomic sequencing has shown that intrahepatic CCA often displays an increased frequency of mutations in genes encoding isocitrate dehydrogenase (IDH, IDH1, IDH2) and Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), fibroblast growth factor receptor (FGFR) 2 gene fusion events, and tumour protein p53 (TP53) mutations whereas extrahepatic CCA often shows an increased frequency of mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) and TP53 [8, 9]
Liver fluke-associated CCA and non-liver fluke-associated CCA appear to have different mutational profiles; liver fluke-associated CCA displays a higher frequency of erb-b2 receptor tyrosine kinase 2 (ERBB2) gene amplification and TP53, and SMAD family member 4 (SMAD4) mutations, and fluke-negative CCA display programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 ligand 2 (PD-L2) protein expression, mutations in IDH1/2 and breast-cancer susceptibility gene 1-associated protein 1 (BAP1), and FGFR-related gene rearrangements [8, 10, 11]
Summary
Current treatment options for CCA have been recently reviewed [1, 5, 22] and here we will only briefly summarise this topic. Surgical resection of CCA offers the potential of curative treatment. This can be followed by adjuvant chemotherapy with capecitabine, a pro-drug which following conversion to 5-fluorouracil, blocks DNA replication by acting as an inhibitor of thymidylate synthase [23]. Leucovorin increases inhibition of thymidylate synthase by 5-fluorouracil resulting in more effective inhibition of DNA replication while oxaliplatin induces DNA damage and blocks DNA replication. None of these treatments target cancer cells and in all cases, drug-resistant cells can emerge through, for example, the up-regulation of DNA damage repair processes [1].
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