TY - JOUR
T1 - Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia
AU - Gebru, Melat T.
AU - Atkinson, Jennifer M.
AU - Young, Megan M.
AU - Zhang, Lijun
AU - Tang, Zhenyuan
AU - Liu, Zhenqiu
AU - Lu, Pinyi
AU - Dower, Christopher M.
AU - Chen, Longgui
AU - Annageldiyev, Charyguly
AU - Sharma, Arati
AU - Kawasawa, Yuka Imamura
AU - Zhao, Zhongming
AU - Miller, Barbara A.
AU - Claxton, David F.
AU - Wang, Hong Gang
N1 - Funding Information:
This work was supported, in part, by National Institutes of Health, National Cancer Institute grants CA171983 and CA222349, the Hyundai Hope on Wheels Foundation, and the Lois High Berstler Research Fund and the Four Diamonds Fund of the Penn State College of Medicine. Technical support was provided by the Cancer Prevention and Research Institute of Texas (grant RP180734 to Z.Z.).
PY - 2020/8/27
Y1 - 2020/8/27
N2 - FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor–dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.
AB - FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained subpopulation of drug-sensitive cells, so-called drug-tolerant "persisters" (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA sequencing and drug screening, we find that treatment of FLT3 internal tandem duplication AML cells with quizartinib, a selective FLT3 inhibitor, upregulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids (GCs). Mechanistically, the combination of FLT3 inhibitors and GCs enhances cell death of FLT3 mutant, but not wild-type, cells through GC-receptor–dependent upregulation of the proapoptotic protein BIM and proteasomal degradation of the antiapoptotic protein MCL-1. Moreover, the enhanced antileukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and GCs has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3-mutant AML.
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U2 - 10.1182/blood.2019003124
DO - 10.1182/blood.2019003124
M3 - Article
C2 - 32396937
AN - SCOPUS:85090079744
VL - 136
SP - 1067
EP - 1079
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -