TY - JOUR
T1 - Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia
AU - Zhang, Haijiao
AU - Nakauchi, Yusuke
AU - Köhnke, Thomas
AU - Stafford, Melissa
AU - Bottomly, Daniel
AU - Thomas, Rozario
AU - Wilmot, Beth
AU - McWeeney, Shannon K.
AU - Majeti, Ravindra
AU - Tyner, Jeffrey W.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s43018-020-0103-x
DO - 10.1038/s43018-020-0103-x
M3 - Article
C2 - 33123685
AN - SCOPUS:85094945517
SN - 2662-1347
VL - 1
SP - 826
EP - 839
JO - Nature Cancer
JF - Nature Cancer
IS - 8
ER -