ArticleOncotarget2015
A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 28 citations in OpenAlex.
- Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer.JAMA oncology · 2018Trial
- Phosphoproteomic Profiling of Multiple Myeloma Based on Ex Vivo Drug Sensitivity Resistance Testing Identifies Phosphorylation Signatures Associated with Drug Response.Biomolecules · 2026Article
- Transfer learning with multiomics integration and deep neural networks reveals drug resistance mechanisms in cancer.Scientific reports · 2025Article
- Combinatorial CRISPR screen revealseLife · 2025Article
- Fyn, an important molecule in the brain, is a potential therapeutic target for brain tumours.Frontiers in pharmacology · 2024Review
- Combination of HDAC and FYN inhibitors in synovial sarcoma treatment.Frontiers in cell and developmental biology · 2024Article
- Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells.Cell proliferation · 2023Article
- FYN: emerging biological roles and potential therapeutic targets in cancer.Journal of translational medicine · 2023Review
- Construction of three-gene-based prognostic signature and analysis of immune cells infiltration in children and young adults with B-acute lymphoblastic leukemia.Molecular genetics & genomic medicine · 2022Article
- Targeting the NRF2/HO-1 Antioxidant Pathway in FLT3-ITD-Positive AML Enhances Therapy Efficacy.Antioxidants (Basel, Switzerland) · 2022Article
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- Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy.International journal of molecular sciences · 2019Review
- Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-κB pathways in a model of chronic myeloid leukemia.Molecular oncology · 2018Article
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- EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids.Cancers · 2017Review
- NADPH Oxidases: Insights into Selected Functions and Mechanisms of Action in Cancer and Stem Cells.Oxidative medicine and cellular longevity · 2017Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Tyrosine kinase inhibitors (TKI) have improved CML response rates, and some are effective against resistance-promoting point mutations in BCR-ABL1. However, in the absence of point mutations, resistance still occurs. Here, we identify a novel pathway mediating resistance which connects p47phox, the organizer subunit of NADPH oxidase-2 (NOX2), with early growth response-1 (Egr-1) and the Src family kinase Fyn. We found up-regulation of p47phox, Egr-1, and Fyn mRNA and protein using paired isogenic CML cell lines and mined data. Isolation of CD34+ cells and tissue microarray staining from blast crisis CML patients confirmed in vivo over-expression of components of this pathway. Knockdown studies revealed that p47phox modulated reactive oxygen species and Egr-1 expression, which, in turn, controlled Fyn expression. Interestingly, Fyn knockdown sensitized TKI-resistant cells to dasatinib, a dual BCR-ABL1/Src inhibitor. Egr-1 knockdown had similar effects, indicating the utility of targeting Fyn expression over activation. Pointedly, p47phox knockdown also restored TKI-sensitivity, indicating that targeting the NOX2 complex can overcome resistance. The NOX2/Egr-1/Fyn pathway was also conserved within TKI-resistant EGFRΔIII-expressing glioblastoma and patient-derived glioblastoma stem cells. Thus, our findings suggest that targeting the NOX2/Egr-1/Fyn pathway may have clinical implications within multiple cancer types; particularly where efficacy of TKI is compromised.
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Registered trials
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.