Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia

Haijiao Zhang, Yusuke Nakauchi, Thomas Köhnke, Melissa Stafford, Daniel Bottomly, Rozario Thomas, Beth Wilmot, Shannon K. McWeeney, Ravindra Majeti, Jeffrey W. Tyner

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Deregulation of the BCL2 gene family plays an important role in the pathogenesis of acute myeloid leukemia (AML). The BCL2 inhibitor, venetoclax, has received FDA approval for the treatment of AML. However, upfront and acquired drug resistance ensues due, in part, to the clinical and genetic heterogeneity of AML, highlighting the importance of identifying biomarkers to stratify patients onto the most effective therapies. By integrating clinical characteristics, exome and RNA sequencing, and inhibitor data from primary AML patient samples, we determined that myelomonocytic leukemia, upregulation of BCL2A1 and CLEC7A, as well as mutations of PTPN11 and KRAS conferred resistance to venetoclax and multiple venetoclax combinations. Venetoclax in combination with an MCL1 inhibitor AZD5991 induced synthetic lethality and circumvented venetoclax resistance.

Original languageEnglish (US)
Pages (from-to)826-839
Number of pages14
JournalNature Cancer
Volume1
Issue number8
DOIs
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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