Co-Targeting of HDAC, PI3K, and Bcl-2 Results in Metabolic and Transcriptional Reprogramming and Decreased Mitochondrial Function in Acute Myeloid Leukemia

Hurrish, Katie Hege; Qiao, Xuguang; Li, Xinyu; Su, Yongwei; Carter, Jenna; Ma, Jun; Kalpage, Hasini A.; Hüttemann, Maik; Edwards, Holly; Wang, Guan; Kim, Seongho; Dombkowski, Alan A.; Bao, Xun; Li, Jing; Taub, Jeffrey W.; Ge, Yubin

doi:10.2139/ssrn.4182539

Cited by 2 publications

(1 citation statement)

References 30 publications

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“…Metabolomics analysis of MV4-11 cells with acquired resistance to AraC (MV4-11/AraC-R 18 ) and the parental MV4-11 cells revealed 100 differentially expressed metabolites (AraC-R data set), and pathway analysis of the AraC-R data set revealed the purine and pyrimidine metabolism pathways among the top pathways affected. 38 Comparing the AraC-R data set and the ME-344 data set, we identified 6 overlapping metabolites that were oppositely modulated. These included AICAR, IMP, and GMP (purine biosynthesis) and UDP-Glc and UDP-GlcNAc (pyrimidine metabolism).…”

Section: Me-344 Enhances the Antileukemic Activity Of Ven Against Ara...mentioning

confidence: 99%

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis

Baran

Hurrish

et al. 2023

Preprint

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Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 synergized with VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, an inhibitor of purine biosynthesis, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired resistance to AraC showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. These results translated into significantly prolonged survival upon combination of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

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Section: Me-344 Enhances the Antileukemic Activity Of Ven Against Ara...mentioning

confidence: 99%

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis

Baran

Hurrish

et al. 2023

Preprint

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Venetoclax Resistance in Acute Myeloid Leukemia

Garciaz,

Hospital,

Collette

et al. 2024

Cancers

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Venetoclax is a BH3-mimetics agent interacting with the anti-apoptotic protein BCL2, facilitating cytochrome c release from mitochondria, subsequent caspases activation, and cell death. Venetoclax combined with azacitidine (VEN-AZA) has become a new standard treatment for AML patients unfit for intensive chemotherapy. In the phase III VIALE-A study, VEN-AZA showed a 65% overall response rate and 14.7 months overall survival in comparison with 22% and 8 months in the azacitidine monotherapy control arm. Despite these promising results, relapses and primary resistance to venetoclax are frequent and remain an unmet clinical need. Clinical and preclinical studies have been conducted to identify factors driving resistance. Among them, the most documented are molecular alterations including IDH, FLT3, TP53, and the newly described BAX mutations. Several non-genetic factors are also described such as metabolic plasticity, changes in anti-apoptotic protein expression, and dependencies, as well as monocytic differentiation status. Strategies to overcome venetoclax resistance are being developed in clinical trials, including triplet therapies with targeted agents targeting IDH, FLT3, as well as the recently developed menin inhibitors or immunotherapies such as antibody–drug conjugated or monoclonal antibodies. A better understanding of the molecular factors driving venetoclax resistance by single-cell analyses will help the discovery of new therapeutic strategies in the future.

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Co-Targeting of HDAC, PI3K, and Bcl-2 Results in Metabolic and Transcriptional Reprogramming and Decreased Mitochondrial Function in Acute Myeloid Leukemia

Cited by 2 publications

References 30 publications

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and purine biosynthesis

Venetoclax Resistance in Acute Myeloid Leukemia

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