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Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia
- Source :
- Nature Cancer, Nature Cancer, 2021, 2 (11), pp.1204-1223. ⟨10.1038/s43018-021-00264-y⟩
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a ‘MitoScore’ signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies. Sarry and colleagues demonstrate that adaptive resistance to venetoclax + cytarabine therapy in acute myeloid leukemia relies on mitochondrial respiration and show that combination with electron transport chain complex inhibitors delays relapse in patient-derived xenograft models in vivo.
- Subjects :
- Cancer Research
Combination therapy
[SDV]Life Sciences [q-bio]
Cell
Oxidative phosphorylation
chemistry.chemical_compound
In vivo
hemic and lymphatic diseases
Medicine
Humans
ComputingMilieux_MISCELLANEOUS
Sulfonamides
business.industry
Venetoclax
Cytarabine
Myeloid leukemia
Pyruvate dehydrogenase complex
Bridged Bicyclo Compounds, Heterocyclic
carbohydrates (lipids)
Leukemia, Myeloid, Acute
medicine.anatomical_structure
Oncology
chemistry
Cancer research
Azacitidine
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 26621347
- Database :
- OpenAIRE
- Journal :
- Nature Cancer, Nature Cancer, 2021, 2 (11), pp.1204-1223. ⟨10.1038/s43018-021-00264-y⟩
- Accession number :
- edsair.doi.dedup.....82b53df2ce4295c18f2bfd97c1ac0618