Overcome Drug Resistance in Cholangiocarcinoma: New Insight Into Mechanisms and Refining the Preclinical Experiment Models

Abstract

Cholangiocarcinoma (CCA) is an aggressive tumor characterized by a poor prognosis. Therapeutic options are limited in patients with advanced stage of CCA, as a result of the intrinsic or acquired resistance to currently available chemotherapeutic agents, and the lack of new drugs entering into clinical application. The challenge in translating basic research to the clinical setting, caused by preclinical models not being able to recapitulate the tumor characteristics of the patient, seems to be an important reason for the lack of effective and specific therapies for CCA. So, there seems to be two ways to improve patient outcomes. The first one is developing the combination therapies based on a better understanding of the mechanisms contributing to the resistance to currently available chemotherapeutic agents. The second one is developing novel preclinical experimental models that better recapitulate the genetic and histopathological features of the primary tumor, facilitating the screening of new drugs for CCA patients. In this review, we discussed the evidence implicating the mechanisms underlying treatment resistance to currently investigated drugs, and the development of preclinical experiment models for CCA.

Keywords: cholangiocarcinoma; drug resistance; mechanisms; patient-derived organoids; research model.

Figure 1

Patient-derived organoid (PDO) model and patient-derived xenograft (PDX) model in precision medicine.

Figure 2

Signaling pathways involved in drug resistance in cholangiocarcinoma. (A) Wnt/β-catenin signal pathway in drug resistance in cholangiocarcinoma: Wnt binds to its receptor-Frizzled to activate Dsh protein, which phosphorylate and inactivate GSK3β, facilitating the translocation of free and unphosphorylated β-catenin from the cytoplasm to the nucleus, where β-catenin binds to TCF/LEF to promote MDR1 expression. (B) Notch signal pathway in drug resistance in cholangiocarcinoma: After Notch activation, γ-secretase (Presenilin and Nicastrin) cleaves Notch COOH-terminal fragment. NICD, released into the cytoplasm, further translocate to the nucleus, where NICD interact with SKIP and CSL, leading to SMRT/HDACs dissociation and converting CSL to a transcriptional activator to initiate the expression of ABCC1, MRP1 and Sox9, which can further promote the expression of ABCB1 and ABCC4. (C) NF-kB signaling pathway in drug resistance in cholangiocarcinoma: NF-kB translocate into the nuclear to initiate the expression of ABCB1, ABCC1 and ABCG2.