Chemoresistance and chemosensitization in cholangiocarcinoma

Abstract

One of the main difficulties in the management of patients with advanced cholangiocarcinoma (CCA) is their poor response to available chemotherapy. This is the result of powerful mechanisms of chemoresistance (MOC) of quite diverse nature that usually act synergistically. The problem is often worsened by altered MOC gene expression in response to pharmacological treatment. Since CCA includes a heterogeneous group of cancers their genetic signature coding for MOC genes is also diverse; however, several shared traits have been defined. Some of these characteristics are shared with other types of liver cancer, namely hepatocellular carcinoma and hepatoblastoma. An important goal in modern oncologic pharmacology is to develop novel strategies to overcome CCA chemoresistance either by increasing drug specificity, such as in targeted therapies aimed to inhibit receptors with tyrosine kinase activity, or to increase the amounts of active agents inside CCA cells by enhancing drug uptake or reducing efflux through export pumps. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

Causes of hOCT1‐Dependent Cholangiocarcinoma Resistance to Sorafenib and Sensitization by Tumor‐Selective Gene Therapy

“…However, data on the effectiveness of sorafenib, and other TKIs, in patients with CCA are controversial, reporting both beneficial effect and poor activity against this type of liver cancer . The latter is not surprising considering the strong multidrug resistance (MDR) phenotype of CCA, in which several MOCs involved in the lack of response to sorafenib have been identified . These include the overexpression of ABC proteins, such as MDR1 and BCRP, which reduce intracellular drug content (MOC‐1b); enhanced drug inactivation by uridine glucuronosyl transferase 1A (MOC‐2); or the appearance of genetic variants in the intracellular targets of sorafenib (MOC‐3) .…”

“…This partly accounts for the very poor prognosis of this cancer, from which most patients die within 12 months after diagnosis. Classical chemotherapy offers a 5‐year survival rate lower than 10%, which is due to the negligible degree of response of all types of CCA to available chemotherapeutic regimens . Gemcitabine plus cisplatin has become the reference regimen for systemic chemotherapy in patients with biliary tract cancers; nonetheless, this chemotherapy is poorly effective.…”

“…Moreover, sorafenib has been reported to have some anticancer activity against CCA in experimental models both in vitro and in vivo , which has not been consistently confirmed in clinical studies . The lack of response of patients with CCA to sorafenib may be the result of the combined action of several mechanisms of chemoresistance (MOCs) . We have demonstrated that the organic cation transporter 1 (hOCT1, SLC22A1 gene) can play a key role in sorafenib effectiveness because the mechanism of action of this drug depends on its access to the intracellular domains of the tyrosine kinases that are inhibited by sorafenib .…”

Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance

“…More than 100 genes involved in chemoresistance have been identified and classified into seven groups of MOC based on their mechanism of action. 189,190…”

Patients with Cholangiocarcinoma Present Specific RNA Profiles in Serum and Urine Extracellular Vesicles Mirroring the Tumor Expression: Novel Liquid Biopsy Biomarkers for Disease Diagnosis

“…CCAs are generally asymptomatic in early stages, being therefore commonly diagnosed in advanced phases when the disease is disseminated. Late diagnosis combined with the chemoresistant nature of these tumors [6] highly compromise the current therapeutic options, mainly based on surgery, significantly impacting on patient's welfare and outcome [1,2]. the diagnosis of CCA is usually conducted by combining clinical, biochemical, radiological, and histological information.…”