Mitochondrial determinants of response and resistance to venetoclaxpluscytarabine duplet therapy in acute myeloid leukemia

Abstract

The development of resistance to conventional and targeted therapy represents a major clinical barrier in treatment of acute myeloid leukemia (AML). We show that the resistance to cytarabine (AraC) and its associated mitochondrial phenotype were reversed by genetic silencing or pharmacological inhibition of BCL2 in a caspase-dependent manner. BCL2-inhibitor venetoclax (VEN) enhancement of AraC efficacy was independent of differentiation phenotype, a characteristic of response to another combination of VEN with hypomethylating agents (HMA). Furthermore, transcriptional profiles of patients with low response to VEN+AraC mirrored those of low responders to VEN+HMA in clinical trials. OxPHOS was found to be a patient stratification marker predictive of effective response to VEN+AraC but not to VEN+AZA. Importantly, whereas three cell subpopulations specifically emerged in VEN+AraC residual disease and were characterized by distinct developmental and transcriptional programs largely driven by MITF, E2F4 and p53 regulons, they each encoded proteins involved in assembly of NADH dehydrogenase complex. Notably, treatment of VEN+AraC-persisting AML cells with an ETCI inhibitor significantly increased the time-to-relapse in vivo. These findings provide the scientific rationale for new clinical trials of VEN+AraC combinations, especially in patients relapsing or non-responsive to chemotherapy, or after failure of frontline VEN+HMA regimen

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

“…In B-progenitor acute lymphoblastic leukemia (B-ALL), diagnosis relapse initiating clones (dRI) transcriptionally enriched for mitochondrial metabolism are present from the diagnosis [ 12 ]. In addition, the direct or indirect inhibition of the electron transport chain (ETC) [ 13 , 14 , 15 ] or the oxidation of substrates such as fatty acids [ 16 ] have proven to be of therapeutic benefit in leukemia, synergizing with AraC or with BCL-2 inhibition [ 17 , 18 ]. One much less studied aspect is the effect of OxPHOS inhibitors in an immunocompetent context, especially in AML, as the vast majority of the studies use NSG mice to allow the study of human cell lines or samples.…”

Rewiring of mitochondrial metabolism in therapy-resistant cancers: permanent and plastic adaptations

“…When treated with venetoclax, an inhibitor of BCL-2, and AraC, the AML cells were sensitive. Furthermore, when AraCresistant AML cells were treated with venetoclax and inhibitors of the ETC, there was delayed relapse (Bosc et al, 2021). Reliance on oxphos through BCL-2 regulation in chemoresistant AML has been shown elsewhere as well (Lagadinou et al, 2013).…”

“…FAO in the resistant cells was revealed to be a targetable vulnerability when FAO was inhibited by siRNAs against FA genes and etomoxir, resulting in increased sensitivity to ven/aza (Stevens et al, 2020). Upregulated FAO gene signatures were also seen in AraC resistant AML cells by single-cell transcriptomics (Bosc et al, 2021).…”

“…In breast cancer, epirubicin resistant cells had increased mitochondrial ATP production which was shown to be a vulnerability upon treatment with biguanide phenformin, an inhibitor of Complex I of the ETC, in cell lines and tumor xenografts (McGuirk et al, 2021). In acute myeloid leukemia (AML), primary cancer cells that were resistant to cytarabine (AraC) and had a high "MitoScore," which identified cells with high reliance on oxphos, were highly reliant on B cell lymphoma-2 (BCL-2) expression (Bosc et al, 2021). When treated with venetoclax, an inhibitor of BCL-2, and AraC, the AML cells were sensitive.…”