ArticleThe Journal of experimental medicine2018
Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies.
Article in The Journal of experimental medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 58 citations in OpenAlex.
- Rewiring KRAS-driven cancers through the ubiquitin-proteasome system: therapeutic opportunities with a focus on deubiquitinase.Experimental & molecular medicine · 2026Review
- Gene dependency-informed inference of response to targeted cancer therapies.Nature communications · 2026Article
- Targeting the deubiquitinase USP28 in cancer: navigating context-dependent mechanisms and therapeutic resistance.Frontiers in immunology · 2026Review
- Targeting ubiquitination in disease and therapy.Signal transduction and targeted therapy · 2025Review
- Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Article
- Effect of deubiquitinases in head and neck squamous cell carcinoma (Review).Oncology letters · 2025Review
- USP10 drives cancer stemness and enables super-competitor signalling in colorectal cancer.Oncogene · 2024Article
- Resveratrol inhibits Lin28A expression and induces its degradation via the proteasomal pathway in NCCIT cells.Oncology letters · 2024Article
- Novel molecular subtypes of intracranial germ cell tumors expand therapeutic opportunities.Neuro-oncology · 2024Article
- SHP2 inhibitors maintain TGFβ signalling through SMURF2 inhibition.NPJ precision oncology · 2023Article
- Deubiquitinases in cancer.Nature reviews. Cancer · 2023Review
- The E3/E4 ubiquitin ligase UFD-2 suppresses normal and oncogenic signaling mediated by a Raf ortholog inScience signaling · 2023Article
- The Highs and Lows of FBXW7: New Insights into Substrate Affinity in Disease and Development.Cells · 2023Review
- Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na).Pharmaceutics · 2023Review
- Ubiquitin-specific protease 28: the decipherment of its dual roles in cancer development.Experimental hematology & oncology · 2023Review
- Protein degradation: expanding the toolbox to restrain cancer drug resistance.Journal of hematology & oncology · 2023Review
- SPOP inhibits BRAF-dependent tumorigenesis through promoting non-degradative ubiquitination of BRAF.Cell & bioscience · 2022Article
- BRAF Inhibitor Resistance in Melanoma: Mechanisms and Alternative Therapeutic Strategies.Current treatment options in oncology · 2022Review
- USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.Molecular oncology · 2022Article
Corrections and comments
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Authors and funding
20 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
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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.