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Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma.

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and it usually occurs following chronic liver disease. Although some progress has been made in the treatment of HCC, the prognosis of patients with advanced HCC is not optimistic, mainly because of the inevitable development of drug resistance. Therefore, multi-target kinase inhibitors for the treatment of HCC, such as sorafenib, lenvatinib, cabozantinib, and regorafenib, produce small clinical benefits for patients with HCC. It is necessary to study the mechanism of kinase inhibitor resistance and explore possible solutions to overcome this resistance to improve clinical benefits. In this study, we reviewed the mechanisms of resistance to multi-target kinase inhibitors in HCC and discussed strategies that can be used to improve treatment outcomes.

SUBMITTER: Jiang L

PROVIDER: S-EPMC9987615 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma.

Jiang Lei L Li Luan L Liu Yongzhuang Y Lu Ligong L Zhan Meixiao M Yuan Shengtao S Liu Yanyan Y

Frontiers in pharmacology 20230213

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and it usually occurs following chronic liver disease. Although some progress has been made in the treatment of HCC, the prognosis of patients with advanced HCC is not optimistic, mainly because of the inevitable development of drug resistance. Therefore, multi-target kinase inhibitors for the treatment of HCC, such as sorafenib, lenvatinib, cabozantinib, and regorafenib, produce small clinical benefits for patients ...[more]

PMID: 36891274

Similar Datasets

Erratum: Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma.

Project description:[This corrects the article DOI: 10.3389/fphar.2023.1097277.].

| S-EPMC10107049 | biostudies-literature

A preliminary study on drug switching strategy for second-line therapy after combination treatment of tyrosine kinase inhibitors and immune checkpoint inhibitors for unresectable hepatocellular carcinoma.

Project description:Background: Combination treatment with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has been widely used in patients with unresectable hepatocellular carcinoma (uHCC). As no standard guidelines exist for second-line therapy after failure of combination treatment, this study aimed to determine a better drug-switching strategy. Methods: A total of 785 patients with uHCC who initially received a combination treatment of TKIs and ICIs between January 2017 and December 2021 at our center were screened. After applying the inclusion and exclusion criteria, a total of 102 patients were included in the study. Based on drug switching strategy, patients were divided into a single drug-switching group (A group, n = 49) and a double drug-switching group (B group, n = 53). The comparative effectiveness between groups A and B was assessed based on treatment response and survival time. Second progression-free survival (SPFS) and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test. Results: Compared to group B, group A had a higher overall response rate (16.3% vs. 3.8%; p = 0.0392) and disease control rate (61.2% vs. 49.1%; p = 0.238). The median SPFS in group A was longer than that in group B (5.47 vs. 3.8 months; HR = 1.70, p = 0.0176). In the second-line therapy, the inclusion of lenvatinib resulted in a better SPFS than other TKI treatments (5.53 vs. 2.83 months, p = 0.0038). Conclusion: After the failure of the combination treatment of TKIs and ICIs, single-drug switching significantly prolonged median SPFS in uHCC patients, and retaining lenvatinib resulted in the survival benefit of single-drug switching.

| S-EPMC9561133 | biostudies-literature

Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies.

Project description:Hepatocellular carcinoma (HCC) is characterized by a growing number of new cases diagnosed each year that is nearly equal to the number of deaths from this cancer. In a majority of the cases, HCC is associated with the underlying chronic liver disease, and it is diagnosed in advanced stage of disease when curative treatment options are not applicable. Sorafenib is a treatment of choice for patients with performance status 1 or 2 and/or macrovascular invasion or extrahepatic spread, and regorafenib is the only systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment. Other drugs tested in different trials failed to demonstrate any benefit. Disappointing results of numerous trials testing the efficacy of various drugs indicate that HCC has low sensitivity to chemotherapy that is in great part caused by multidrug resistance. Immunotherapy for HCC is a new challenging treatment option and involves immune checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another challenging approach is microRNA-based therapy that involves two strategies. The first aims to inhibit oncogenic miRNAs by using miRNA antagonists and the second strategy is miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function.

| S-EPMC5513853 | biostudies-literature

Pharmacoproteomics Identifies Kinase Pathways that Drive the Epithelial-Mesenchymal Transition and Drug Resistance in Hepatocellular Carcinoma.

Project description:Hepatocellular carcinoma (HCC) is a complex and deadly disease lacking druggable genetic mutations. The limited efficacy of systemic treatments for advanced HCC implies that predictive biomarkers and drug targets are urgently needed. Most HCC drugs target protein kinases, indicating that kinase-dependent signaling networks drive HCC progression. To identify HCC signaling networks that determine responses to kinase inhibitors (KIs), we apply a pharmacoproteomics approach integrating kinome activity in 17 HCC cell lines with their responses to 299 KIs, resulting in a comprehensive dataset of pathway-based drug response signatures. By profiling patient HCC samples, we identify signatures of clinical HCC drug responses in individual tumors. Our analyses reveal kinase networks promoting the epithelial-mesenchymal transition (EMT) and drug resistance, including a FZD2-AXL-NUAK1/2 signaling module, whose inhibition reverses the EMT and sensitizes HCC cells to drugs. Our approach identifies cancer drug targets and molecular signatures of drug response for personalized oncology.

| S-EPMC7484106 | biostudies-literature

Molecular Bases of Drug Resistance in Hepatocellular Carcinoma.

Project description: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.

| S-EPMC7352164 | biostudies-literature

Angiogenesis Inhibitors for the Treatment of Hepatocellular Carcinoma.

Project description:Background: Angiogenesis inhibitors have become an important therapeutic approach in the treatment of hepatocellular carcinoma (HCC) patients. The therapeutic inhibition of angiogenesis of Sorafenib in increasing overall survival of patients with HCC is a fundamental element of the treatment of this disease. Considering the heterogeneous aspects of HCC and to boost therapeutic efficacy, prevail over drug resistance and lessen toxicity, adding antiangiogenic drugs to antiblastic chemotherapy (AC), radiation therapy or other targeted drugs have been evaluated. The matter is additionally complicated by the combination of antiangiogenesis with further AC or biologic drugs. To date, no planned approach to understand which patients are more responsive to a given type of antiangiogenic treatment is available. Conclusion: Large investments in the clinical research are essential to improve treatment response and minimize toxicities for patients with HCC. Future investigations will need to focus on utilizing patterns of genetic information to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapies with AC producing enhanced anti-tumor effect. In this review the current panel of available antiangiogenic therapies for the treatment of HCC have been analyzed. In addition current clinical trials are also reported herein.

| S-EPMC5101236 | biostudies-literature

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers.

Project description:Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK/pUL97). Here, we expand this finding by further assessing the in vitro synergistic antiviral interaction between vCDK and CDK inhibitors towards HCMV as well as non-human cytomegaloviruses. An extension of this synergy approach was achieved in vivo by using the recombinant MCMV-UL97/mouse model, confirming the high potential of combination treatment with the clinically approved vCDK inhibitor maribavir (MBV) and the developmental CDK7 inhibitor LDC4297. Moreover, mechanistic aspects of this synergistic drug combination were illustrated on the levels of intracellular viral protein transport and viral genome replication. The analysis of viral drug resistance did not reveal resistance formation in the case of MBV + LDC4297 combination treatment. Spanning various investigational levels, these new results strongly support our concept, employing the great potential of anti-HCMV synergistic drug treatment.

| S-EPMC10748244 | biostudies-literature

The pharmacogenomics of drug resistance to protein kinase inhibitors.

Project description:Dysregulation of growth factor cell signaling is a major driver of most human cancers. This has led to development of numerous drugs targeting protein kinases, with demonstrated efficacy in the treatment of a wide spectrum of cancers. Despite their high initial response rates and survival benefits, the majority of patients eventually develop resistance to these targeted therapies. This review article discusses examples of established mechanisms of drug resistance to anticancer therapies, including drug target mutations or gene amplifications, emergence of alternate signaling pathways, and pharmacokinetic variation. This reveals a role for pharmacogenomic analysis to identify and monitor for resistance, with possible therapeutic strategies to combat chemoresistance.

| S-EPMC5022787 | biostudies-literature

MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma.

Project description:Primary liver cancer [hepatocellular carcinoma (HCC)] is one of the most common malignant tumors worldwide, causing serious health threats because of its high morbidity and mortality, rapid growth, and strong invasiveness. Patients with HCC frequently develop resistance to the current chemotherapeutic drugs, and this is largely attributed to the high-level heterogeneity of the tumor tissue. MicroRNAs (miRNAs) are a group of master regulators for multiple physiological and pathological processes and play important roles in the tumorigenesis. More recent studies have indicated that miRNAs also play a non-negligible role in the development of drug resistance in liver cancer. In this review, we summarize the data from the latest studies on the mechanisms of drug resistance in liver cancer, including autophagy, membrane transporters, epithelial-mesenchymal transitions (EMTs), tumor microenvironment, and genes and proteins that are associated with apoptosis. The data herein will provide valuable information for the development of novel approaches to tackle drug resistance in the management of liver cancer.

| S-EPMC7338562 | biostudies-literature

Pharmacoproteomics identifies kinase pathways that drive the epithelial-mesenchymal transition and drug resistance in hepatocellular carcinoma

Project description:Hepatocellular carcinoma (HCC) is a complex and deadly disease lacking druggable genetic mutations. The limited efficacy of systemic treatments for advanced HCC implies that novel predictive biomarkers and drug targets are urgently needed. Most HCC drugs target protein kinases and their kinase-dependent signaling networks to drive HCC progression. To identify HCC signaling networks that determine responses to kinase inhibitors (KIs), we apply a pharmacoproteomics approach integrating kinome activity in 17 HCC cell lines with their responses to 299 KIs, resulting in a comprehensive dataset of pathway-based drug response signatures. By profiling patient HCC samples, we identify signatures of clinical HCC drug responses in individual tumors. Our analyses reveal kinase networks promoting the epithelial-mesenchymal transition (EMT) and drug resistance, including a FZD2-AXL-NUAK1/2 signaling module, whose inhibition reverses the EMT and sensitizes HCC cells to drugs. Our approach identifies cancer drug targets and molecular signatures of drug response for personalized oncology.

2018-12-15 | MSV000083236 | MassIVE

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