髓系白血病
文
威尼斯人
阿扎胞苷
白血病
癌症研究
干细胞
医学
化学
药理学
内科学
生物
生物化学
基因
慢性淋巴细胞白血病
遗传学
DNA甲基化
基因表达
计算机科学
计算机安全
作者
Brett M. Stevens,Courtney L. Jones,Daniel A. Pollyea,Rachel Culp‐Hill,Angelo D’Alessandro,Amanda Winters,Anna Krug,Madeline Goosman,Shanshan Pei,Haobin Ye,Austin E. Gillen,Michael W. Becker,Michael R. Savona,Clayton A. Smith,Craig T. Jordan
出处
期刊:Nature cancer
[Springer Nature]
日期:2020-10-26
卷期号:1 (12): 1176-1187
被引量:129
标识
DOI:10.1038/s43018-020-00126-z
摘要
Venetoclax with azacitidine (ven/aza) has emerged as a promising regimen for acute myeloid leukemia (AML), with a high percentage of clinical remissions in newly diagnosed patients. However, approximately 30% of newly diagnosed and the majority of relapsed patients do not achieve remission with ven/aza. 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. Herein we demonstrate that resistance to ven/aza occurs via up-regulation of fatty acid oxidation (FAO), which occurs due to RAS pathway mutations, or as a compensatory adaptation in relapsed disease. Utilization of FAO obviates the need for amino acid metabolism, thereby rendering ven/aza ineffective. Pharmacological inhibition of FAO restores sensitivity to ven/aza in drug resistant AML cells. We propose inhibition of FAO as a therapeutic strategy to address ven/aza resistance.
科研通智能强力驱动
Strongly Powered by AbleSci AI