ArticleLeukemia2015
The γ-secretase inhibitor PF-03084014 combined with fludarabine antagonizes migration, invasion and angiogenesis in NOTCH1-mutated CLL cells.
Article in Leukemia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 69 citations in OpenAlex.
- Pilot evaluation of optical genome mapping in chronic lymphocytic leukemia: complementing FISH analysis.BMC cancer · 2025Article
- Advancing the therapeutic effectiveness of paclitaxel in chronic lymphocytic leukemia through the simultaneous inhibition of NOTCH1 and SF3B1.Cancer cell international · 2025Article
- The Role of RAC2 and PTTG1 in Cancer Biology.Cells · 2025Review
- Recent Advances in Signaling Pathways and Kinase Inhibitors for Leukemia Chemotherapy.Current medicinal chemistry · 2025Review
- Insights into genetic aberrations and signalling pathway interactions in chronic lymphocytic leukemia: from pathogenesis to treatment strategies.Biomarker research · 2024Review
- CAD204520 TargetsInternational journal of molecular sciences · 2024Article
- Secretase promotes AD progression: simultaneously cleave Notch and APP.Frontiers in aging neuroscience · 2024Review
- High-resolution Melting Analysis for NOTCH1 c.7541-7542delCT Mutation in Chronic Lymphocytic Leukemia: Prognostic Significance in Egyptian Patients.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2022Article
- Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond.Cancers · 2022Review
- Targeting Notch to Maximize Chemotherapeutic Benefits: Rationale, Advanced Strategies, and Future Perspectives.Cancers · 2021Review
- Impaired nodal shrinkage and apoptosis define the independent adverse outcome of NOTCH1 mutated patients under ibrutinib therapy in chronic lymphocytic leukaemia.Haematologica · 2021Article
- Perspectives on Precision Medicine in Chronic Lymphocytic Leukemia: Targeting Recurrent Mutations-NOTCH1, SF3B1, MYD88, BIRC3.Journal of clinical medicine · 2021Review
- Therapeutic Targeting of the Leukaemia Microenvironment.International journal of molecular sciences · 2021Review
- Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets.Cancers · 2021Review
- Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma.Scientific reports · 2021Article
- Genomic profiling of CD20 negative diffuse large B cell lymphoma identifies targetable mutations: A case report.EJHaem · 2020Article
- Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies.Haematologica · 2020Review
- Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL.Cells · 2020Article
- Genetics of "high-risk" chronic lymphocytic leukemia in the times of chemoimmunotherapy.Haematologica · 2020Article
- Notch1 signaling in NOTCH1-mutated mantle cell lymphoma depends on Delta-Like ligand 4 and is a potential target for specific antibody therapy.Journal of experimental & clinical cancer research : CR · 2019Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Targeting Notch signaling has emerged as a promising therapeutic strategy for chronic lymphocytic leukemia (CLL), especially for the poor prognostic subgroup of NOTCH1-mutated patients. Here, we report that the γ-secretase inhibitor PF-03084014 inhibits the constitutive Notch activation and induces selective apoptosis in CLL cells carrying NOTCH1 mutations. Combination of PF-03084014 with fludarabine has a synergistic antileukemic effect in primary NOTCH1-mutated CLL cells, even in the presence of the protective stroma. At transcriptional level, PF-03084014 plus fludarabine treatment induces the upregulation of the proapoptotic gene HRK and the downmodulation of MMP9, IL32 and RAC2 genes that are related to invasion and chemotaxis. PF-03084014 also overcomes fludarabine-mediated activation of nuclear factor-κB signaling. Moreover, this combination impairs angiogenesis and CXCL12-induced responses in NOTCH1-mutated CLL cells, in particular those related to tumoral migration and invasion. Importantly, all these collaborative effects are specific for NOTCH1 mutation and do not occur in unmutated cases. In conclusion, we provide evidence that Notch is a therapeutic target in CLL cases with NOTCH1-activating mutations, supporting the use of Notch pathway inhibitors in combination with chemotherapy as a promising approach for the treatment of these high-risk CLL patients.
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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.