ArticleMolecular cancer2013
Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.
Article in Molecular cancer, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 56 citations in OpenAlex.
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- Molecular Classification and Overcoming Therapy Resistance for Acute Myeloid Leukemia with Adverse Genetic Factors.International journal of molecular sciences · 2022Review
- Biomarker LEPRE1 induces pelitinib-specific drug responsiveness by regulating ABCG2 expression and tumor transition states in human leukemia and lung cancer.Scientific reports · 2022Article
- Dual Kinase Targeting in Leukemia.Cancers · 2021Review
- NVP-BEZ235 or JAKi Treatment leads to decreased survival of examined GBM and BBC cells.Cancer treatment and research communications · 2021Article
- A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia.BMC pharmacology & toxicology · 2020Article
- Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways.Molecules (Basel, Switzerland) · 2020Review
- Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias.International journal of molecular sciences · 2020Review
- Alternative splicing of the tumor suppressor ASPP2 results in a stress-inducible, oncogenic isoform prevalent in acute leukemia.EBioMedicine · 2019Article
- SESN2 negatively regulates cell proliferation and casein synthesis by inhibition the amino acid-mediated mTORC1 pathway in cow mammary epithelial cells.Scientific reports · 2018Article
- EGFR-TKIs resistance via EGFR-independent signaling pathways.Molecular cancer · 2018Review
- Pantoprazole Induces Apoptosis of Leukemic Cells by Inhibiting Expression of P-Glycoprotein/Multidrug Resistance-Associated Protein-1 Through PI3K/AKT/mTOR Signaling.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2017Article
- Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.Cancer biology & therapy · 2017Article
- High-Throughput Phenotypic Screening of Kinase Inhibitors to Identify Drug Targets for Polycystic Kidney Disease.SLAS discovery : advancing life sciences R & D · 2017Article
- Review
- Healthy CD4+ T lymphocytes are not affected by targeted therapies against the PI3K/Akt/mTOR pathway in T-cell acute lymphoblastic leukemia.Oncotarget · 2016Article
- Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns.BMC cancer · 2016Article
- Tudor-SN Regulates Milk Synthesis and Proliferation of Bovine Mammary Epithelial Cells.International journal of molecular sciences · 2015Article
- Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer.Oncotarget · 2015Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDysregulation of the PI3Kinase/AKT pathway is involved in the pathogenesis of many human malignancies. In acute leukemia, the AKT pathway is frequently activated, however mutations in the PI3K/AKT pathway are uncommon. In some cases, constitutive AKT activation can be linked to gain-of-function tyrosine kinase (TK) mutations upstream of the PI3K/AKT pathway. Inhibitors of the PI3K/AKT pathway are attractive candidates for cancer drug development, but so far clinical efficacy of PI3K inhibitors against various neoplasms has been moderate. Furthermore, specific MTORC1 inhibitors, acting downstream of AKT, have the disadvantage of activating AKT via feed-back mechanisms. We now evaluated the antitumor efficacy of NVP-BGT226, a novel dual pan-PI3K and MTORC1/2 inhibitor, in acute leukemia.
methodsNative leukemia blasts were stained to analyze for AKT phosphorylation levels on a flow cytometer. Efficacy of NVP-BGT226 in comparison to a second dual inhibitor, NVP-BEZ235, was determined with regard to cellular proliferation, autophagy, cell cycle regulation and induction of apoptosis in in vitro and ex vivo cellular assays as well as on the protein level. An isogenic AKT-autoactivated Ba/F3 model, different human leukemia cell lines as well as native leukemia patient blasts were studied. Isobologram analyses were set up to calculate for (super) additive or antagonistic effects of two agents.
resultsWe show, that phosphorylation of AKT is frequently augmented in acute leukemia. NVP-BGT226 as well as NVP-BEZ235 profoundly and globally suppress AKT signaling pathways, which translates into potent antiproliferative effects. Furthermore, NVP-BGT226 has potent proapoptotic effects in vitro as well as in ex vivo native blasts. Surprisingly and in contrast, NVP-BEZ235 leads to a profound G1/G0 arrest preventing significant induction of apoptosis. Combination with TK inhibitors, which are currently been tested in the treatment of acute leukemia subtypes, overcomes cell cycle arrest and results in (super)additive proapoptotic effects for NVP-BGT226--but also for NVP-BEZ235. Importantly, mononuclear donor cells show lower phospho-AKT expression levels and consequently, relative insensitivity towards dual PI3K-MTORC1/2 inhibition.
conclusionsOur data suggest a favorable antileukemic profile for NVP-BGT226 compared to NVP-BEZ235--which provides a strong rationale for clinical evaluation of the dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia.
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