ArticleBMC systems biology2018
Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma.
Article in BMC systems biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 37 citations in OpenAlex.
- Comprehensive overview of AI methodologies in nano-drug delivery Optimization and Design.NPJ precision oncology · 2026Review
- Therapeutic Potential of Glutaminase Inhibition Targeting Metabolic Adaptations in Resistant Melanomas to Targeted Therapy.International journal of molecular sciences · 2025Article
- Medulloblastoma's master regulators and their association with patients' risk.Scientific reports · 2025Article
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- BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers.Cancers · 2023Review
- p53 Family in Resistance to Targeted Therapy of Melanoma.International journal of molecular sciences · 2022Review
- Tetrabromobisphenol A effects on differentiating mouse embryonic stem cells reveals unexpected impact on immune system.Frontiers in genetics · 2022Article
- Article
- Identification of pathways modulating vemurafenib resistance in melanoma cells via a genome-wide CRISPR/Cas9 screen.G3 (Bethesda, Md.) · 2021Article
- Review
- Systems level profiling of arginine starvation reveals MYC and ERK adaptive metabolic reprogramming.Cell death & disease · 2020Article
- Autocrine/paracrine actions of growth hormone in human melanoma cell lines.Biochemistry and biophysics reports · 2020Article
- A Novel Aptamer LL4A Specifically Targets Vemurafenib-Resistant Melanoma through Binding to the CD63 Protein.Molecular therapy. Nucleic acids · 2019Article
- Opportunities for Artificial Intelligence in Advancing Precision Medicine.Current genetic medicine reports · 2019Article
- Targeting transcription factors in cancer - from undruggable to reality.Nature reviews. Cancer · 2019Review
- CD271 is a molecular switch with divergent roles in melanoma and melanocyte development.Scientific reports · 2019Article
- Concurrent Targeting of Glutaminolysis and Metabotropic Glutamate Receptor 1 (GRM1) Reduces Glutamate Bioavailability in GRM1Cancer research · 2019Article
- Review
- Emerging roles of H3K9me3, SETDB1 and SETDB2 in therapy-induced cellular reprogramming.Clinical epigenetics · 2019Review
- Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundKinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma.
methodsThe cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non-genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential.
resultsDownregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors.
conclusionsThe established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer.
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