期刊
ANTIOXIDANTS
卷 11, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/antiox11040717
关键词
FLT3-ITD; TKI resistance; HO-1; NRF2; AML
资金
- National Institutes of Health through MD Anderson's Cancer Center Support Grant [P30 CA016672, F32 CA171905, R01 CA115811]
- division of Pediatrics
- Cancer Prevention & Research Institute of Texas [CPRIT: RP150006]
- National Cancer Institute [R01CA138816]
AML patients with FLT3-ITD mutations have elevated levels of HO-1, which contributes to TKI resistance. Inhibiting HO-1 can increase sensitivity to TKI and genetic or pharmacological suppression of NRF2, a key driver of the pathway, results in decreased HO-1 levels and reduced AML resistance.
Acute myeloid leukemia (AML) is a molecularly heterogenous hematological malignancy, with one of the most common mutations being internal tandem duplication (ITD) of the juxtamembrane domain of the fms-like tyrosine kinase receptor-3 (FLT3). Despite the development of FLT3-directed tyrosine kinase inhibitors (TKI), relapse and resistance are problematic, requiring improved strategies. In both patient samples and cell lines, FLT3-ITD raises levels of reactive oxygen species (ROS) and elicits an antioxidant response which is linked to chemoresistance broadly in AML. NF-E2-related factor 2 (NRF2) is a transcription factor regulating the antioxidant response including heme oxygenase -1 (HO-1), a heat shock protein implicated in AML resistance. Here, we demonstrate that HO-1 is elevated in FLT3-ITD-bearing cells compared to FLT3-wild type (WT). Transient knockdown or inhibitor-based suppression of HO-1 enhances vulnerability to the TKI, quizartinib, in both TKI-resistant and sensitive primary AML and cell line models. NRF2 suppression (genetically or pharmacologically using brusatol) results in decreased HO-1, suggesting that TKI-resistance is dependent on an active NRF2-driven pathway. In AML-patient derived xenograft (PDX) models, brusatol, in combination with daunorubicin, reduces leukemia burden and prolongs survival. Cumulatively, these data encourage further development of brusatol and NRF2 inhibition as components of combination therapy for refractory AML.
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