ArticleBlood2010
Multiple distinct molecular mechanisms influence sensitivity and resistance to MDM2 inhibitors in adult acute myelogenous leukemia.
Article in Blood, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 83 citations in OpenAlex.
- The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.Haematologica · 2012Trial
- Patients with AML with WT TP53 but defective TP53-mediated apoptosis have a dismal survival.JCI insight · 2026Article
- Star wars against leukemia: attacking the clones.Leukemia · 2024Review
- Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.Cancer medicine · 2024Article
- Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: immune escape mechanisms and current implications for therapy.Molecular cancer · 2023Review
- Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Review
- Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with doxorubicin in A549 cells.Scientific reports · 2023Article
- Mechanical phenotyping reveals unique biomechanical responses in retinoic acid-resistant acute promyelocytic leukemia.iScience · 2022Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Design, Synthesis, Chemical and Biochemical Insights Into Novel Hybrid Spirooxindole-Based p53-MDM2 Inhibitors With Potential Bcl2 Signaling Attenuation.Frontiers in chemistry · 2021Article
- Targeting Apoptosis in Acute Myeloid Leukemia: Current Status and Future Directions of BCL-2 Inhibition with Venetoclax and Beyond.Targeted oncology · 2020Review
- Targeting Apoptotic Pathways in Acute Myeloid Leukaemia.Cancers · 2019Review
- Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia.Nature communications · 2019Article
- Targeting the GFI1/1B-CoREST Complex in Acute Myeloid Leukemia.Frontiers in oncology · 2019Review
- MDM2 antagonists as a novel treatment option for acute myeloid leukemia: perspectives on the therapeutic potential of idasanutlin (RG7388).OncoTargets and therapy · 2019Review
- Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy.Cancer discovery · 2018Article
- MDM2- and FLT3-inhibitors in the treatment ofHaematologica · 2018Article
- Lanthanide-doped nanoparticles conjugated with an anti-CD33 antibody and a p53-activating peptide for acute myeloid leukemia therapy.Biomaterials · 2018Article
- Article
- Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition.Cancer research · 2018Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 2 countries.
Funding
Abstract
The survival of most patients with acute myelogenous leukemia (AML) remains poor, and novel therapeutic approaches are needed to improve outcomes. Given that the fraction of AML with mutated p53 is small ( approximately 10%), it appears rational to study MDM2 inhibitors as therapy for AML. Here, we report results of a detailed characterization of sensitivity and resistance to treatment ex vivo with the MDM2 inhibitor MI219 in AML blasts from 109 patients. In line with previous observations, all AML cases with mutated p53 were resistant to MI219. Importantly, approximately 30% of AML cases with unmutated p53 also demonstrated primary resistance to MI219. Analysis of potential mechanisms associated with MI219 resistance in AML blasts with wild-type p53 uncovered distinct molecular defects, including low or absent p53 protein induction after MDM2 inhibitor treatment or external irradiation. Furthermore, a separate subset of resistant blasts displayed robust p53 protein induction after MI219 treatment, indicative of defective p53 protein function or defects in the apoptotic p53 network. Finally, analysis of very sensitive AML cases uncovered a strong and significant association with mutated Flt3 status (Flt3-ITD), which for the first time identified a clinically high-risk group of AML that may particularly benefit from MDM2 inhibitor treatment.
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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.