Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle-regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. .
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712262 | PMC |
| http://dx.doi.org/10.1158/0008-5472.CAN-17-0899 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Influence of Ageing on the Pharmacodynamics and Pharmacokinetics of Chronically Administered Medicines in Geriatric Patients: A Review.
Clin Pharmacokinet
January 2025
Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Durban, South Africa.
As people age, the efficiency of various regulatory processes that ensure proper communication between cells and organs tends to decline. This deterioration can lead to difficulties in maintaining homeostasis during physiological stress. This includes but is not limited to cognitive impairments, functional difficulties, and issues related to caregivers which contribute significantly to medication errors and non-adherence.
View Article and Find Full Text PDFTranscription factor MAZ activates the transcription of hypomethylated TYMP in ccRCC.
Funct Integr Genomics
January 2025
School of Medical Technology, Tianjin Medical University, Tianjin, 300203, China.
Clear cell renal cell carcinoma (ccRCC) is a highly malignant tumor characterized by a significant propensity for recurrence and metastasis. DNA methylation has emerged as a critical epigenetic mechanism with substantial utility in cancer diagnosis. In this study, multi-omics data were utilized to investigate the target genes regulated by the transcription factor MYC-associated zinc finger protein (MAZ) in ccRCC, leading to the identification of thymidine phosphorylase (TYMP) as a gene with notably elevated expression in ccRCC.
View Article and Find Full Text PDFIL-33, a neutrophil extracellular trap-related gene involved in the progression of diabetic kidney disease.
Inflamm Res
January 2025
Department of Nephrology, First Affiliated Hospital of Naval Medical University, Shanghai Changhai Hospital, Shanghai, China.
Background: Chronic inflammation is well recognized as a key factor related to renal function deterioration in patients with diabetic kidney disease (DKD). Neutrophil extracellular traps (NETs) play an important role in amplifying inflammation. With respect to NET-related genes, the aim of this study was to explore the mechanism of DKD progression and therefore identify potential intervention targets.
View Article and Find Full Text PDFA Challenging Case of IgG4-Related Kidney Disease Accompanied With Positive Serologic Tests of Lupus Erythematosus.
Nephrology (Carlton)
January 2025
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.
The case report presents a male patient in his mid-60s with a history of hypertension, benign prostatic hyperplasia and chronic kidney disease (CKD). He presented with gradually increasing serum creatinine levels and hyperglobulinemia, leading to suspicion of multiple myeloma. However, subsequent testing revealed features consistent with systemic lupus erythematosus (SLE) and IgG4-related kidney disease (IgG4-RKD).
View Article and Find Full Text PDFEvaluation of a potential bidirectional influence of metabolic syndrome and apical periodontitis: An animal-based study.
Int Endod J
January 2025
Department of Integrated Clinical Procedures, School of Dentistry, Rio de Janeiro State University (UERJ), Rio de Janeiro, Brazil.
Aim: This study aimed to explore the possible bidirectional interrelations between fructose-induced metabolic syndrome (MS) and apical periodontitis (AP).
Methodology: Twenty-eight male Wistar rats were distributed into four groups (n = 7, per group): Control (C), AP, Fructose Consumption (FRUT) and Fructose Consumption and AP (FRUT+AP). The rats in groups C and AP received filtered water, while those in groups FRUT and FRUT+AP received a 20% fructose solution mixed with water to induce MS.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!