ArticleMolecular cancer research : MCR2016
Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma.
Article in Molecular cancer research : MCR, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 32 citations in OpenAlex.
- Targeting replication stress in neuroblastoma by exploiting the synergistic potential of second generation RRM2 and CHK1 inhibitors.Cell death & disease · 2026Article
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- A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer.PloS one · 2024Article
- Delineating the glioblastoma stemness by genes involved in cytoskeletal rearrangements and metabolic alterations.World journal of stem cells · 2023Review
- RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition.Science advances · 2022Article
- From DNA Copy Number Gains and Tumor Dependencies to Novel Therapeutic Targets for High-Risk Neuroblastoma.Journal of personalized medicine · 2021Review
- Identification of candidate biomarkers correlated with poor prognosis of breast cancer based on bioinformatics analysis.Bioengineered · 2021Article
- Identification of subgroups along the glycolysis-cholesterol synthesis axis and the development of an associated prognostic risk model.Human genomics · 2021Article
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- Cyclin F is involved in response to cisplatin treatment in melanoma cell lines.Oncology reports · 2020Article
- Comprehensive Analysis of Differential Gene Expression to Identify Common Gene Signatures in Multiple Cancers.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- Article
- Proteomic Level Changes on Treatment in MCF-7/DDP Breast Cancer Drug- Resistant Cells.Anti-cancer agents in medicinal chemistry · 2020Article
- Bioinformatics analysis revealing prognostic significance ofBioscience reports · 2019Article
- Identification of Potential Biomarkers in Glioblastoma through Bioinformatic Analysis and Evaluating Their Prognostic Value.BioMed research international · 2019Article
- Ribonucleotide reductase subunit M2 as a novel target for clear-cell renal cell carcinoma.OncoTargets and therapy · 2019Article
- Potential role of cyclin F mRNA expression in the survival of skin melanoma patients: Comprehensive analysis of the pathways altered due to cyclin F upregulation.Oncology reports · 2018Article
- Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease.Frontiers in endocrinology · 2018Review
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledThe majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest. IMPLICATIONS: Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma. Mol Cancer Res; 14(9); 767-75. ©2016 AACR.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.