ArticleClinical cancer research : an official journal of the American Association for Cancer Research2016
Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 80 citations in OpenAlex.
- Review
- The Role of the PI3K/Akt/mTOR Axis in Head and Neck Squamous Cell Carcinoma.Biomedicines · 2024Review
- JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia.iScience · 2023Article
- Review
- Bim downregulation by activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance in multiple myeloma cells.Clinical and experimental medicine · 2023Article
- Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia.HemaSphere · 2023Review
- Review
- Review
- Review
- Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy.Molecular biomedicine · 2022Review
- Article
- Either IL-7 activation of JAK-STAT or BEZ inhibition of PI3K-AKT-mTOR pathways dominates the single-cell phosphosignature ofHaematologica · 2022Article
- MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance.Leukemia · 2021Article
- Pan-PI3Ki targets multiple B-ALL microenvironment interactions that fuel systemic and CNS relapse.Leukemia & lymphoma · 2021Article
- Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells.International journal of molecular sciences · 2021Article
- Dual Mechanisms of Metabolism and Gene Expression of the CCRF-CEM Leukemia Cells under Glucocorticoid Treatment.International journal of molecular sciences · 2021Article
- Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells.Molecular medicine reports · 2021Article
- The Role of mTOR Signaling as a Therapeutic Target in Cancer.International journal of molecular sciences · 2021Review
- Hypoxia favors chemoresistance in T-ALL through an HIF1α-mediated mTORC1 inhibition loop.Blood advances · 2021Article
- Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol.Frontiers in oncology · 2021Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
purposeThe aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in acute lymphoblastic leukemia (ALL). EXPERIMENTAL
designThe cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry, and immunoprecipitation.
resultsInhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the proapoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression.
conclusionsOur data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.
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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.