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Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

ABSTRACT: The combination of venetoclax with azacitidine (ven/aza) has recently emerged as a promising regimen for acute myeloid leukemia (AML), with approximately 70% of newly diagnosed patients achieving complete remission (CR). However, 30% of newly diagnosed and nearly all relapsed patients do not achieve CR with ven/aza. Mechanistically, we previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. In the present study we demonstrate that resistance to ven/aza occurs as a consequence of up-regulated fatty acid oxidation (FAO), which occurs either as an intrinsic property of RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism into the TCA cycle, thereby rendering ven/aza ineffective. Importantly, we show that pharmacological inhibition of FAO via use of MCL-1 or CPT1 inhibitor drugs restores targeting of ven/aza resistant AML stem cells. Based on these findings we propose that inhibition of FAO is a potential therapeutic strategy to address ven/aza resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156008 | GEO | 2020/08/17

REPOSITORIES: GEO

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Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

Project description:The combination of venetoclax with azacitidine (ven/aza) has recently emerged as a promising regimen for acute myeloid leukemia (AML), with approximately 70% of newly diagnosed patients achieving complete remission (CR). However, 30% of newly diagnosed and nearly all relapsed patients do not achieve CR with ven/aza. Mechanistically, we previously reported that ven/aza efficacy is based on eradication of AML stem cells through a mechanism involving inhibition of amino acid metabolism, a process which is required in primitive AML cells to drive oxidative phosphorylation. In the present study we demonstrate that resistance to ven/aza occurs as a consequence of up-regulated fatty acid oxidation (FAO), which occurs either as an intrinsic property of RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism into the TCA cycle, thereby rendering ven/aza ineffective. Importantly, we show that pharmacological inhibition of FAO via use of MCL-1 or CPT1 inhibitor drugs restores targeting of ven/aza resistant AML stem cells. Based on these findings we propose that inhibition of FAO is a potential therapeutic strategy to address ven/aza resistance.

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Targeting SUMOylation sensitizes Acute myeloid leukemia to Venetoclax treatment

Project description:Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism.

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Project description:Deep single-cell multi-omic profiling of drug resistance in patients with relapsed or refractory (rr) acute myeloid leukemia (AML) is a promising approach to understand and identify the molecular and cellular determinants of drug resistance. Here, we address this challenge by integrating single-cell ex vivo drug profiling (pharmacoscopy) with both bulk and single-cell resolved DNA, RNA, and protein profiling, as well as clinical annotations across samples of a cohort of 21 rrAML patients. Unsupervised data integration revealed ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) to be significantly reduced in patients treated with the combination of a hypomethylating agent (HMA) and VEN compared to patients pre-exposed to HMA only, while also exposing innate Ven resistance in a subset of VEN-naive patients. Systematic molecular integration retrieved known and novel molecular mechanisms underlying VEN resistance and identified alternative therapeutic strategies in VEN resistant samples, including targeting increased proliferation by PLK inhibitor volasertib. Across data modalities, high CD36 expression on AML blasts was associated with VENres, while CD36-targeted antibody treatment ex vivo revealed striking sensitivity in VEN resistant AML. In summary, we showcase how single-cell multi-omic and functional profiling can facilitate the discovery of drug resistance mechanisms and emergent treatment vulnerabilities. Our dataset represents a comprehensive molecular and functional profiling of rrAML at single-cell resolution, providing a valuable resource for future studies.

| MSV000092970 | MassIVE

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