Resistance to Therapy in Liver and Gastrointestinal Tumors

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 32173

Special Issue Editors

Experimental Hepatology and Drug Targeting, University of Salamanca, IBSAL, CIBERehd, 37007 Salamanca, Spain
Interests: hepatology; chemoresistance; drug targeting; biomarkers; biliary cancer
Experimental Hepatology and Drug Targeting, University of Salamanca, IBSAL, Salamanca, Spain
Interests: Hepatology, Experimental Pharmacology; Chemoresistance; Drug targeting
Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), University of Salamanca, Campus Miguel de Unamuno E.D. Lab231, 37007 Salamanca, Spain
Interests: liver cancer; bile acids; chemoresistance; drug targeting; ABC protein; hepatology; pathophysiology; pharmacology

Special Issue Information

Dear Colleagues,

Resistance to chemotherapy is a major problem for patients with most types of liver and gastrointestinal cancers (LGICs). Tumor cells can be resistant to chemotherapy before the administration of drugs (intrinsic resistance) or can be initially sensitive to drugs and develop resistance during treatment (acquired resistance). The mechanisms behind the failure of chemotherapy include changes in transport proteins involved in drug uptake and efflux, changes in enzymes responsible for drug metabolism, mutations in drug targets, enhanced DNA repair damage, activation of survival-signaling pathways, the effect of factors related to tumor cell microenvironment, or the activation of epithelial–mesenchymal transition. Moreover, LGICs are formed by a heterogeneous population of malignant cells that are subjected to Darwinian selection, which contributes to overall chemoresistance. In this sense, the presence of cancer stem cells plays a key role in the appearance of chemoresistance. A better understanding of the mechanisms of chemoresistance can be useful for future drug development, to choose combinations of drugs to improve their efficacy in selected patients and to design strategies to overcome chemoresistance.

This Special Issue aims to compile original research and review articles dealing with advances taking place in the area of chemoresistance research in LGICs, with special interest in articles describing mechanisms of resistance to treatments, identification of biomarkers associated with response to therapy, experimental models to study drug resistance, prognostic factors, strategies to overcome drug resistance, treatments based on molecular targets, and novel drug development.

Prof. Rocio I.R. Macias
Prof. Oscar Briz
Prof. Dr. Jose J.G. Marin
Guest Editors

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Keywords

  • biliary cancer
  • chemoresistance
  • colon cancer
  • gastric cancer
  • hepatoblastoma
  • hepatocellular carcinoma
  • pancreas cancer

Published Papers (9 papers)

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Research

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21 pages, 2881 KiB  
Article
High-Risk Clinicopathological and Genetic Features and Outcomes in Patients Receiving Neoadjuvant Radiochemotherapy for Locally Advanced Rectal Cancer
by Sofía del Carmen, Luís Antonio Corchete, Cristina González Velasco, Julia Sanz, José Antonio Alcazar, Jacinto García, Ana Isabel Rodríguez, Rosario Vidal Tocino, Alba Rodriguez, Luis Alberto Pérez-Romasanta, José María Sayagués and Mar Abad
Cancers 2021, 13(13), 3166; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133166 - 24 Jun 2021
Cited by 3 | Viewed by 2263
Abstract
Administering preoperative radiochemotherapy (RCT) in stage II-III tumors to locally advanced rectal carcinoma patients has proved to be effective in a high percentage of cases. Despite this, 20–30% of patients show no response or even disease progression. At present, preoperative response is assessed [...] Read more.
Administering preoperative radiochemotherapy (RCT) in stage II-III tumors to locally advanced rectal carcinoma patients has proved to be effective in a high percentage of cases. Despite this, 20–30% of patients show no response or even disease progression. At present, preoperative response is assessed by a combination of imaging and tumor regression on histopathology, but recent studies suggest that various genetic abnormalities may be associated with the sensitivity or resistance of rectal cancer tumor cells to neoadjuvant therapy. In the present study we investigated the relationship between genetic lesions detected by high-density single-nucleotide polymorphisms (SNP) arrays 6.0 and response to neoadjuvant RCT, evaluated according to Dworak criteria in 39 rectal cancer tumors before treatment. The highest frequency of copy-number (CN) losses detected corresponded to chromosomes 18q (n = 27; 69%), 1p (n = 22; 56%), 15q (n = 19; 49%), 8p (n = 18; 48%), 4q (n = 17; 46%), and 22q (n = 17; 46%); in turn, CN gains more frequently involved chromosomes 20p (n = 22; 56%), 8p (n = 20; 51%), and 15q (n = 16; 41%). There was a significant association between alterations in the 1p, 3q, 7q, 12p, 17q, 20p, and 22q chromosomal regions and the degree of response to therapy prior to surgery. However, 4q, 15q11.1, and 15q14 chromosomal region alterations were identified as important by five prediction algorithms, i.e., those with the greatest influence on predicting the tumor response to treatment with preoperative RCT. Multivariate analysis of prognostic factors showed that gains on 15q11.1 and carcinoembryonic antigen (CEA) levels serum at diagnosis were the only independent variables predicting disease-free survival (DFS). Lymph node involvement also showed a prognostic impact on overall survival (OS) in the multivariate analysis. A deep-learning-based algorithm showed a 100% success rate in predicting both DFS and OS at 60 months after diagnosis of the disease. In summary, our results indicate the existence of an association between tumor genetic abnormalities at diagnosis, response to neoadjuvant therapy, and survival of patients with locally advanced rectal cancer. In addition to the clinical and biological characteristics of locally advanced rectal cancer patients, these could be used in the future as therapeutic and prognostic biomarkers, to identify patients sensitive or resistant to preoperative treatment, helping guide therapeutic decision-making. Additional prospective studies in larger series of patients are required to confirm the clinical utility of the newly identified biomarkers. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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17 pages, 2616 KiB  
Article
The Human TOR Signaling Regulator Is the Key Indicator of Liver Cancer Patients’ Overall Survival: TIPRL/LC3/CD133/CD44 as Potential Biomarkers for Early Liver Cancers
by Soo Young Jun, Hyang Ran Yoon, Ji-Yong Yoon, Su-Jin Jeon, Jeong-Ju Lee, Debasish Halder, Jin-Man Kim and Nam-Soon Kim
Cancers 2021, 13(12), 2925; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13122925 - 11 Jun 2021
Cited by 2 | Viewed by 2113
Abstract
Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we [...] Read more.
Recently, we reported the involvement of TIPRL/LC3/CD133 in liver cancer aggressiveness. This study assessed the human TOR signaling regulator (TIPRL)/microtubule-associated light chain 3 (LC3)/prominin-1 (CD133)/cluster of differentiation 44 (CD44) as potential diagnostic and prognostic biomarkers for early liver cancer. For the assessment, we stained tissues of human liver disease/cancer with antibodies against TIPRL/LC3/CD133/CD44/CD46, followed by confocal observation. The roles of TIPRL/LC3/CD133/CD44/CD46 in liver normal and cancer cell lines were determined by in vitro studies. We analyzed the prognostic and diagnostic potentials of TIPRL/LC3/CD133/CD44/CD46 using the receiver-operating characteristic curve, a Kaplan–Meier and uni-/multi-Cox analyses. TIPRL and LC3 were upregulated in tissues of HCCs and adult hepatocytes-derived liver diseases while downregulated in iCCA. Intriguingly, TIPRL levels were found to be critically associated with liver cancer patients’ survivability, and TIPRL is the key player in liver cancer cell proliferation and viability via stemness and self-renewal induction. Furthermore, we demonstrate that TIPRL/LC3/CD133 have shown prominent efficiency for diagnosing patients with grade 1 iCCA. TIPRL/LC3/CD133/CD44 have also provided excellent potential for prognosticating patients with grade 1 iCCA and grade 1 HCCs, together with demonstrating that TIPRL/LC3/CD133/CD44 are, either individually or in conjunction, potential biomarkers for early liver cancer. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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14 pages, 3994 KiB  
Article
MicroRNA-199b Downregulation Confers Resistance to 5-Fluorouracil Treatment and Predicts Poor Outcome and Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Patients
by Ion Cristóbal, Jaime Rubio, Andrea Santos, Blanca Torrejón, Cristina Caramés, Laura Imedio, Sofía Mariblanca, Melani Luque, Marta Sanz-Alvarez, Sandra Zazo, Juan Madoz-Gúrpide, Federico Rojo and Jesús García-Foncillas
Cancers 2020, 12(6), 1655; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061655 - 22 Jun 2020
Cited by 14 | Viewed by 2020
Abstract
Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers [...] Read more.
Neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy followed by mesorectal excision is the current standard treatment in locally advanced rectal cancer (LARC) and the lack of complete response represents a major problem that compromises long-term patient survival. However, there is a lack of robust established markers predictive of response to this preoperative treatment available in the clinical routine. The tumor suppressor microRNA (miR)-199b directly targets the PP2A inhibitor SET, which has been involved in 5-FU resistance, and its downregulation has been found to correlate with poor outcome in metastatic colorectal cancer. Here, we studied the functional effects of miR-199b on 5-FU sensitivity after its ectopic modulation, and its expression was quantified by real-time-PCR in a cohort of 110 LARC patients to evaluate its potential clinical significance. Interestingly, our findings demonstrate that miR-199b enhances the sensitivity of colorectal cancer cells to 5-FU in a SET-dependent manner, and that both miR-199b overexpression and SET inhibition are able to overcome resistance to this drug using an acquired 5-FU-resistant model. MiR-199b was found downregulated in 26.4% of cases and was associated with positive lymph node levels after chemoradiotherapy (CRT, p = 0.007) and high pathological stage (p = 0.029). Moreover, miR-199b downregulation determined shorter overall (p = 0.003) and event-free survival (p = 0.005), and was an independent predictor of poor response to preoperative CRT (p = 0.004). In conclusion, our findings highlight the clinical impact of miR-199b downregulation predicting poor outcome and pathological response in LARC, and suggest the miR-199b/SET signaling axis as a novel molecular target to prevent the development of resistance to 5-FU treatment. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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Review

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26 pages, 3468 KiB  
Review
Genomic Heterogeneity of Pancreatic Ductal Adenocarcinoma and Its Clinical Impact
by María Laura Gutiérrez, Luis Muñoz-Bellvís and Alberto Orfao
Cancers 2021, 13(17), 4451; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174451 - 03 Sep 2021
Cited by 15 | Viewed by 3009
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities—i.e., classical vs. squamous subtypes of PDAC—leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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18 pages, 694 KiB  
Review
Genetic Heterogeneity, Therapeutic Hurdle Confronting Sorafenib and Immune Checkpoint Inhibitors in Hepatocellular Carcinoma
by Sara M. Atwa, Margarete Odenthal and Hend M. El Tayebi
Cancers 2021, 13(17), 4343; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174343 - 27 Aug 2021
Cited by 9 | Viewed by 2629
Abstract
Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase [...] Read more.
Despite the latest advances in hepatocellular carcinoma (HCC) screening and treatment modalities, HCC is still representing a global burden. Most HCC patients present at later stages to an extent that conventional curative options are ineffective. Hence, systemic therapy represented by the tyrosine kinase inhibitor, sorafenib, in the first-line setting is the main treatment modality for advanced-stage HCC. However, in the two groundbreaking phase III clinical trials, the SHARP and Asia-Pacific trials, sorafenib has demonstrated a modest prolongation of overall survival in almost 30% of HCC patients. As HCC develops in an immune-rich milieu, particular attention has been placed on immune checkpoint inhibitors (ICIs) as a novel therapeutic modality for HCC. Yet, HCC therapy is hampered by the resistance to chemotherapeutic drugs and the subsequent tumor recurrence. HCC is characterized by substantial genomic heterogeneity that has an impact on cellular response to the applied therapy. And hence, this review aims at giving an insight into the therapeutic impact and the different mechanisms of resistance to sorafenib and ICIs as well as, discussing the genomic heterogeneity associated with such mechanisms. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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24 pages, 404 KiB  
Review
Stereotactic Radiotherapy for Hepatocellular Carcinoma, Radiosensitization Strategies and Radiation-Immunotherapy Combination
by Luis A. Pérez-Romasanta, Elisabet González-Del Portillo, Ana Rodríguez-Gutiérrez and Ángela Matías-Pérez
Cancers 2021, 13(2), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13020192 - 07 Jan 2021
Cited by 25 | Viewed by 3683
Abstract
Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative [...] Read more.
Stereotactic body radiotherapy (SBRT) is an emerging ablative modality for hepatocellular carcinoma (HCC). Most patients with HCC have advanced disease at the time of diagnosis, and therefore, are not candidates for definitive-intent therapies such as resection or transplantation. For this reason, various alternative local and regional therapies have been used to prevent disease progression, palliate symptoms, and delay liver failure. Stereotactic body radiation therapy is a non-invasive technique of delivering ablative doses of radiation to tumors while sparing normal or non-tumor hepatic tissue. Incorporation of SBRT in multidisciplinary HCC management is gradual, initially applied when other liver-directed therapies have failed or are contraindicated, and tried in combination with other locoregional or systemic therapies for more unfavorable conditions by more experienced teams. In order to improve SBRT therapeutic ratio, there has been much interest in augmenting the effect of radiation on tumors by combining it with chemotherapy, molecularly targeted therapeutics, nanoparticles, and immunotherapy. This review aims to synthesize available evidence to evaluate the clinical feasibility and efficacy of SBRT for HCC, and to explore novel radio-potentiation concepts by combining SBRT with novel therapeutics. It is expected that those approaches would result in improved therapeutic outcomes, even though many questions remain with regard to the optimal way to assemble treatments. Further trials are needed to evaluate and consolidate these promising therapies for HCC. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
34 pages, 1096 KiB  
Review
Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment
by Jose J.G. Marin, Rocio I.R. Macias, Maria J. Monte, Elisa Herraez, Ana Peleteiro-Vigil, Beatriz Sanchez de Blas, Paula Sanchon-Sanchez, Alvaro G. Temprano, Ricardo A. Espinosa-Escudero, Elisa Lozano, Oscar Briz and Marta R. Romero
Cancers 2020, 12(9), 2605; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12092605 - 11 Sep 2020
Cited by 18 | Viewed by 4943
Abstract
The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination [...] Read more.
The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes). Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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29 pages, 863 KiB  
Review
Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma
by Jose J. G. Marin, Laura Perez-Silva, Rocio I. R. Macias, Maitane Asensio, Ana Peleteiro-Vigil, Anabel Sanchez-Martin, Candela Cives-Losada, Paula Sanchon-Sanchez, Beatriz Sanchez De Blas, Elisa Herraez, Oscar Briz and Elisa Lozano
Cancers 2020, 12(8), 2116; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12082116 - 30 Jul 2020
Cited by 32 | Viewed by 4231
Abstract
Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying [...] Read more.
Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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26 pages, 848 KiB  
Review
Molecular Bases of Drug Resistance in Hepatocellular Carcinoma
by Jose J.G. Marin, Rocio I.R. Macias, Maria J. Monte, Marta R. Romero, Maitane Asensio, Anabel Sanchez-Martin, Candela Cives-Losada, Alvaro G. Temprano, Ricardo Espinosa-Escudero, Maria Reviejo, Laura H. Bohorquez and Oscar Briz
Cancers 2020, 12(6), 1663; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061663 - 23 Jun 2020
Cited by 86 | Viewed by 5832
Abstract
The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors [...] Read more.
The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments. Full article
(This article belongs to the Special Issue Resistance to Therapy in Liver and Gastrointestinal Tumors)
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