威尼斯人
髓系白血病
阿扎胞苷
髓样
癌症研究
医学
白血病
肿瘤科
内科学
慢性淋巴细胞白血病
生物
基因
遗传学
基因表达
DNA甲基化
作者
Christopher A. Eide,Stephen E. Kurtz,Andy Kaempf,Nicola Long,Sunil Kumar Joshi,Tamilla Nechiporuk,Ariane Huang,Charles A. Dibb,Akosha Taylor,Daniel Bottomly,Shannon K. McWeeney,Jessica Minnier,Curtis A. Lachowiez,Jennifer N. Saultz,Ronan T. Swords,Anupriya Agarwal,Bill H. Chang,Brian J. Druker,Jeffrey W. Tyner
出处
期刊:Blood cancer discovery
[American Association for Cancer Research]
日期:2023-09-11
卷期号:4 (6): 452-467
被引量:4
标识
DOI:10.1158/2643-3230.bcd-23-0014
摘要
Abstract The BCL2 inhibitor venetoclax combined with the hypomethylating agent azacytidine shows significant clinical benefit in a subset of patients with acute myeloid leukemia (AML); however, resistance limits response and durability. We prospectively profiled the ex vivo activity of 25 venetoclax-inclusive combinations on primary AML patient samples to identify those with improved potency and synergy compared with venetoclax + azacytidine (Ven + azacytidine). Combination sensitivities correlated with tumor cell state to discern three patterns: primitive selectivity resembling Ven + azacytidine, monocytic selectivity, and broad efficacy independent of cell state. Incorporation of immunophenotype, mutation, and cytogenetic features further stratified combination sensitivity for distinct patient subtypes. We dissect the biology underlying the broad, cell state–independent efficacy for the combination of venetoclax plus the JAK1/2 inhibitor ruxolitinib. Together, these findings support opportunities for expanding the impact of venetoclax-based drug combinations in AML by leveraging clinical and molecular biomarkers associated with ex vivo responses. Significance: By mapping drug sensitivity data to clinical features and tumor cell state, we identify novel venetoclax combinations targeting patient subtypes who lack sensitivity to Ven + azacytidine. This provides a framework for a taxonomy of AML informed by readily available sets of clinical and genetic features obtained as part of standard care. See related commentary by Becker, p. 437 . This article is featured in Selected Articles from This Issue, p. 419
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