Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.

  • Platform LUXGEN - Micro-Array
  • Platform Bioinformatics
November 11, 2021 By:
  • Bosc C
  • Saland E
  • Bousard A
  • Gadaud N
  • Sabatier M
  • Cognet G
  • Farge T
  • Boet E
  • Gotanègre M
  • Aroua N
  • Mouchel P-L
  • Polley N
  • Larrue C
  • Kaphan E
  • Picard M
  • Sahal A
  • Jarrou L
  • Tosolini M
  • Rambow F
  • Cabon F
  • Nicot N
  • Poillet-Perez L
  • Wang Y
  • Su X
  • Fovez Q
  • Kluza J
  • Argüello RJ
  • Mazzotti C
  • Avet-Loiseau H
  • Vergez F
  • Tamburini J
  • Fournié J-J
  • Tiong IS
  • Wei AH
  • Kaoma T
  • Marine J-C
  • Récher C
  • Stuani L
  • Joffre C
  • Sarry J-E.

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.

2021 Nov. Nat Cancer.2(11):1204-1223.
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