ArticleThe Journal of biological chemistry2014
Mitogen-activated protein kinase (MAPK) hyperactivation and enhanced NRAS expression drive acquired vemurafenib resistance in V600E BRAF melanoma cells.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 62 citations in OpenAlex.
- Novel insights into extracellular vesicles: An update on biomolecules, immunomodulation and clinical strategies in skin melanoma.Clinical and translational medicine · 2026Review
- Characterization of two melanoma cell lines resistant to BRAF/MEK inhibitors (vemurafenib and cobimetinib).Cell communication and signaling : CCS · 2024Article
- Overcoming Vemurafenib Resistance in Metastatic Melanoma: Targeting Integrins to Improve Treatment Efficacy.International journal of molecular sciences · 2024Article
- Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2.International journal of molecular sciences · 2023Review
- A Predictive Model of Adaptive Resistance to BRAF/MEK Inhibitors in Melanoma.International journal of molecular sciences · 2023Article
- PLX4032 resistance of patient-derived melanoma cells: crucial role of oxidative metabolism.Frontiers in oncology · 2023Article
- Vemurafenib Drives Epithelial-to-Mesenchymal Transition Gene Expression in BRAF Inhibitor‒Resistant BRAFThe Journal of investigative dermatology · 2022Article
- Article
- The pleiotropic roles of circular and long noncoding RNAs in cutaneous melanoma.Molecular oncology · 2022Review
- A Theranostic Cellulose Nanocrystal-Based Drug Delivery System with Enhanced Retention in Pulmonary Metastasis of Melanoma.Small (Weinheim an der Bergstrasse, Germany) · 2021Article
- Review
- Rational Combination Therapy for Melanoma with Dinaciclib by Targeting BAK-Dependent Cell Death.Molecular cancer therapeutics · 2020Article
- Targeting Oncogenic BRAF: Past, Present, and Future.Cancers · 2019Review
- Clinical Implications of NRAS Overexpression in Resectable Pancreatic Adenocarcinoma Patients.Pathology oncology research : POR · 2019Article
- Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma.Journal of experimental & clinical cancer research : CR · 2018Article
- Isolation and characterization of two canine melanoma cell lines: new models for comparative oncology.BMC cancer · 2018Article
- Therapeutic strategies to target RAS-mutant cancers.Nature reviews. Clinical oncology · 2018Review
- Article
- Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma.OncoTargets and therapy · 2018Review
- Identification of NRAS isoform 2 overexpression as a mechanism facilitating BRAF inhibitor resistance in malignant melanoma.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Although targeting the V600E activating mutation in the BRAF gene, the most common genetic abnormality in melanoma, has shown clinical efficacy in melanoma patients, response is, invariably, short lived. To better understand mechanisms underlying this acquisition of resistance to BRAF-targeted therapy in previously responsive melanomas, we induced vemurafenib resistance in two V600E BRAF+ve melanoma cell lines, A375 and DM443, by serial in vitro vemurafenib exposure. The resulting approximately 10-fold more vemurafenib-resistant cell lines, A375rVem and D443rVem, had higher growth rates and showed differential collateral resistance to cisplatin, melphalan, and temozolomide. The acquisition of vemurafenib resistance was associated with significantly increased NRAS levels in A375rVem and D443rVem, increased activation of the prosurvival protein, AKT, and the MAPKs, ERK, JNK, and P38, which correlated with decreased levels of the MAPK inhibitor protein, GSTP1. Despite the increased NRAS, whole exome sequencing showed no NRAS gene mutations. Inhibition of all three MAPKs and siRNA-mediated NRAS suppression both reversed vemurafenib resistance significantly in A375rVem and DM443rVem. Together, the results indicate a mechanism of acquired vemurafenib resistance in V600E BRAF+ve melanoma cells that involves increased activation of all three human MAPKs and the PI3K pathway, as well as increased NRAS expression, which, contrary to previous reports, was not associated with mutations in the NRAS gene. The data highlight the complexity of the acquired vemurafenib resistance phenotype and the challenge of optimizing BRAF-targeted therapy in this disease. They also suggest that targeting the MAPKs and/or NRAS may provide a strategy to mitigate such resistance in V600E BRAF+ve melanoma.
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