Treatment of FLT3-ITD AML with FLT3 inhibitors results in upregulation of inflammatory pathways in drug-tolerant persisters (DTPs).
Anti-inflammatory glucocorticoids in combination with FLT3 inhibitors decrease DTPs by upregulating BIM and downregulating MCL-1.
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 sub-population 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, here we report that treatment of FLT3-ITD AML cells with quizartinib, a selective FLT3 inhibitor, up-regulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids. Mechanistically, the combination of FLT3 inhibitors and glucocorticoids enhances cell death of FLT3 mutant but not wild-type cells through glucocorticoid receptor-dependent upregulation of the pro-apoptotic protein BIM and proteasomal degradation of the anti-apoptotic protein MCL-1. Moreover, the enhanced anti-leukemic 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 glucocorticoids has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3 mutant AML.