{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T03:38:11Z","timestamp":1784259491119,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,12]],"date-time":"2023-01-12T00:00:00Z","timestamp":1673481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["1R01CA197991-01A1"],"award-info":[{"award-number":["1R01CA197991-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.<\/jats:p>","DOI":"10.3390\/cancers15020484","type":"journal-article","created":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T02:29:57Z","timestamp":1673576997000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"15","author":[{"given":"Rebecca","family":"Anderson","sequence":"first","affiliation":[{"name":"Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin M.","family":"Pladna","sequence":"additional","affiliation":[{"name":"Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel J.","family":"Schramm","sequence":"additional","affiliation":[{"name":"Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances B.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Kridel","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy S.","family":"Pardee","sequence":"additional","affiliation":[{"name":"Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest Baptist Health, Medical Center Boulevard, Winston-Salem, NC 27157, USA"},{"name":"Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC 27157, USA"},{"name":"Cornerstone Pharmaceuticals Inc., Cranbury, NJ 08512, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41408-020-00376-1","article-title":"New directions for emerging therapies in acute myeloid leukemia: The next chapter","volume":"10","author":"Daver","year":"2020","journal-title":"Blood Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1200\/JCO.2014.55.1564","article-title":"Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Adults","volume":"32","author":"Klepin","year":"2014","journal-title":"J. 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