Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Marin, José J.G.; Macı́as, Rocı́o I.R.; Monte, María J.; Romero, Marta R.; Asensio, Maitane; Sánchez-Martín, Anabel; Cives-Losada, Candela; Temprano, Alvaro G; Espinosa-Escudero, Ricardo; Reviejo, Maria; Bohorquez, Laura H; Briz, Óscar

doi:10.3390/cancers12061663

Cited by 140 publications

(72 citation statements)

References 184 publications

(233 reference statements)

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“…Sorafenib is an oral inhibitor of vascular endothelial growth factor receptors 2 and 3 (VEGFR-2/3), platelet-derived growth factor receptor β (PDGFR-β), and oncogenic kinases KIT, B-RAF, and C-RAF, that has shown a limited effect in advanced CCA as a single agent [42,43]. Poor efficacy of sorafenib has been partially attributed to low intracellular concentrations in tumor cells due to impaired OCT1-mediated uptake [44] and enhanced MRP3-mediated efflux [45,46] (Table 2). Regorafenib inhibits angiogenic (VEGFR-1-3, TIE2) and stromal (PDGFR-β, fibroblast growth factor receptor 1 or FGFR1) factors that promote tumor vessel formation and suppresses several oncogenic kinases (KIT, RET, RAF) [56] and has shown promising results in advanced refractory CCA [47,57].…”

Section: Multikinase Inhibitorsmentioning

confidence: 99%

Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

Marin

Sanchon-Sanchez

Cives-Losada

et al. 2021

Cancers

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Despite the crucial advances in understanding the biology of cholangiocarcinoma (CCA) achieved during the last decade, very little of this knowledge has been translated into clinical practice. Thus, CCA prognosis is among the most dismal of solid tumors. The reason is the frequent late diagnosis of this form of cancer, which makes surgical removal of the tumor impossible, together with the poor response to standard chemotherapy and targeted therapy with inhibitors of tyrosine kinase receptors. The discovery of genetic alterations with an impact on the malignant characteristics of CCA, such as proliferation, invasiveness, and the ability to generate metastases, has led to envisage to treat these patients with selective inhibitors of mutated proteins. Moreover, the hope of developing new tools to improve the dismal outcome of patients with advanced CCA also includes the use of small molecules and antibodies able to interact with proteins involved in the crosstalk between cancer and immune cells with the aim of enhancing the immune system’s attack against the tumor. The lack of effect of these new therapies in some patients with CCA is associated with the ability of tumor cells to continuously adapt to the pharmacological pressure by developing different mechanisms of resistance. However, the available information about these mechanisms for the new drugs and how they evolve is still limited.

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Section: Multikinase Inhibitorsmentioning

confidence: 99%

Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

Marin

Sanchon-Sanchez

Cives-Losada

et al. 2021

Cancers

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“…Cancer stem cells are considered to maintain stemness for a long period, similarly to tissue stem cells. They divide more slowly than daughter cells, and thus, they are resistant to conventional anti-cancer drugs or radiotherapy ( Figure 2 ) [ 63 ]. Furthermore, it has been suggested that these cells exhibit relatively strong resistance to molecular targeted drugs [ 64 ].…”

Section: Cancer Stem Cells and Pdxsmentioning

confidence: 99%

Patient-Derived Tumor Xenograft Models: Toward the Establishment of Precision Cancer Medicine

Goto

2020

JPM

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Patient-derived xenografts (PDXs) describe models involving the implantation of patient-derived tumor tissue into immunodeficient mice. Compared with conventional preclinical models involving the implantation of cancer cell lines into mice, PDXs can be characterized by the preservation of tumor heterogeneity, and the tumor microenvironment (including stroma/vasculature) more closely resembles that in patients. Consequently, the use of PDX models has improved the predictability of clinical therapeutic responses to 80% or greater, compared with approximately 5% for existing models. In the future, molecular biological analyses, omics analyses, and other experiments will be conducted using recently prepared PDX models under the strong expectation that the analysis of cancer pathophysiology, stem cells, and novel treatment targets and biomarkers will be improved, thereby promoting drug development. This review outlines the methods for preparing PDX models, advances in cancer research using PDX mice, and perspectives for the establishment of precision cancer medicine within the framework of personalized cancer medicine.

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“…HCC is a heterogeneous malignancy with complex carcinogenesis. Although there has been tremendous progress in the treatment of hepatocellular carcinoma over the past decades, the acquisition of chemoresistance continues to be a major hindrance in chemotherapy and targeted-based treatment of the disease [5] , and resistance to these treatments can be subcategorized into intrinsic and acquired. Intrinsic resistance is pre-existent before chemotherapy, thus inducing certain treatments useless.…”

Section: Introductionmentioning

confidence: 99%

The Effect of 2D and 3D Cell Cultures on E-Cadherin Profile and Drug Resistance in Huh7 Cell

Shao

Zou

et al. 2021

Preprint

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Studies have validated three-dimensional (3D) culture of cells differs significantly from the two-dimensional (2D) model in terms of drug efficacy due to complex mechanisms, including up-regulation of drug efflux, acquisition of stem cell-like properties by the cancer cells, aberrant apoptotic, etc. This study aimed to delineate the change of expression profile of E-cadherin in hepatoma cells Huh7 under the 3D condition and 2D condition. Cells were culture in ultra-low attachment plates to form multicellular 3D spheroids. The expression profile of E-cadherin and drug resistance were compared between 2D monolayers and 3D spheroids. E-cadherin was located at cell boundaries and cell membrane in 3D spheroids of Huh7 cells, however, E-cadherin was expressed on the cytoplasm and nuclei in 2D monolayers. In addition, high expression of E-cadherin and hepatic stem cell markers were found in 3D spheroids, and 3D spheroids showed greater resistance to pharmacological compounds. It seems 3D culture promoted the membrane localization of E-cadherin, and the change of MDR-related markers enhanced resistance in Huh7 3D spheroids. This study increases the knowledge of the effect of 3D arrangement in cancer cells.

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Molecular Bases of Drug Resistance in Hepatocellular Carcinoma

Cited by 140 publications

References 184 publications

Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

Novel Pharmacological Options in the Treatment of Cholangiocarcinoma: Mechanisms of Resistance

Patient-Derived Tumor Xenograft Models: Toward the Establishment of Precision Cancer Medicine

The Effect of 2D and 3D Cell Cultures on E-Cadherin Profile and Drug Resistance in Huh7 Cell

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