The DOI matches its Crossref record; 243 of the 243 references it cites were found in a registry or an index.
Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways
Open accessAbstract
Targeted therapy and immunotherapy have greatly improved the prognosis of patients with metastatic melanoma, but resistance to these therapeutic modalities limits the percentage of patients with long-lasting responses. Accumulating evidence indicates that a persisting subpopulation of melanoma cells contributes to resistance to targeted therapy or immunotherapy, even in patients who initially have a therapeutic response; however, the root mechanism of resistance remains elusive. To address this problem, we propose a new model, in which dynamic fluctuations of protein expression at the single-cell level and longitudinal reshaping of the cellular state at the cell-population level explain the whole process of therapeutic resistance development. Conceptually, we focused on two different pivotal signalling pathways (mediated by microphthalmia-associated transcription factor (MITF) and IFNγ) to construct the evolving trajectories of melanoma and described each of the cell states. Accordingly, the development of therapeutic resistance could be divided into three main phases: early survival of cell populations, reversal of senescence, and the establishment of new homeostatic states and development of irreversible resistance. On the basis of existing data, we propose future directions in both translational research and the design of therapeutic strategies that incorporate this emerging understanding of resistance.
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“De-differentiation is exemplified by colon carcinogenesis (due to the loss of the differentiation-inducing transcription factor HOXA5 and SMAD4), 141,142 melanomagenesis (due to the loss of the transcription factor MITF), 143 or pancreatic neuroendocrine tumors (due to the loss of a differentiation-inducing miRNA in b cells).144”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [143]
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Background
Metadata
- Authors
- Bai, X., Fisher, D. E., & Flaherty, K. T.
- Affiliations
- Harvard University (US)
- Corresponding author
- Flaherty, Keith T.
- Venue
- Nature Reviews Clinical Oncology
- Published
- 2019-04-09
- Volume
- 16
- Issue
- 9
- Pages
- 549-562
- ISSN
- 1759-4774 (ISSN-L)
- 1759-4782
- PMC
- PMC7185899
- OpenAlex
- W2936119023
- Cited by
- 107
- References
- 243
- Citations by year
- 2026: 7 · 2025: 20 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 24 · 2020: 20 · 2019: 10
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (U54CA224068, P01CA163222)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR043369)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, treatment resistance, MITF, interferon-gamma, cell state dynamics, targeted therapy resistance, immunotherapy resistance, metastatic melanoma
- MeSH terms
- Humans, Interferon-gamma, Melanoma, Models, Biological, Signal Transduction, Drug Resistance, Neoplasm, Microphthalmia-Associated Transcription Factor
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