P300/CBP inhibition with inobrodib in combination with gilteritinib and venetoclax targets leukemia stem cells in epigenetic mutant AML.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42139346.
- Also identified by DOI 10.1126/sciadv.aec9305 and PMC identifier 13178526.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Acute myeloid leukemia (AML) is a fatal blood cancer with cytotoxic chemotherapy offering at best 25% 5-year survival. While targeted BCL2 and FLT3 inhibitors venetoclax and gilteritinib are used upfront in the treatment of a subset of adult patients with AML and help to extend the survival of some patients, a curative treatment combination with minimal side effects has yet to be discovered. We find that use of the dual histone acetyltransferase p300/CBP bromodomain inhibitor CCS1477 (inobrodib), together with venetoclax and gilteritinib, virtually eliminates leukemia stem cells in an aggressive preclinical model of <i>DNMT3A/FLT3</i>-mutant AML by impairing pro-oncogenic survival and proliferation factors to effectively block leukemogenesis. This work identifies potential clinical utility of a targeted, triplet combination therapy for treatment of AML.
Medical subject headings
- Sulfonamides
- Leukemia, Myeloid, Acute
- Bridged Bicyclo Compounds, Heterocyclic
- Neoplastic Stem Cells
- Mutation
- p300-CBP Transcription Factors
- Aniline Compounds
- Epigenesis, Genetic
- Antineoplastic Combined Chemotherapy Protocols