Glucocorticoids enhance the antileukemic activity of FLT3 inhibitors in FLT3-mutant acute myeloid leukemia

• Published in: Blood 2020-08, Vol.136 (9), p.1067-1079
• Main Authors: Gebru, Melat T., Atkinson, Jennifer M., Young, Megan M., Zhang, Lijun, Tang, Zhenyuan, Liu, Zhenqiu, Lu, Pinyi, Dower, Christopher M., Chen, Longgui, Annageldiyev, Charyguly, Sharma, Arati, Imamura Kawasawa, Yuka, Zhao, Zhongming, Miller, Barbara A., Claxton, David F., Wang, Hong-Gang
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis Regulatory Proteins - biosynthesis; Apoptosis Regulatory Proteins - genetics; Bcl-2-Like Protein 11 - biosynthesis; Bcl-2-Like Protein 11 - genetics; Benzothiazoles - pharmacology; Benzothiazoles - therapeutic use; Computer Simulation; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Drug Resistance, Neoplasm; Drug Synergism; fms-Like Tyrosine Kinase 3 - antagonists & inhibitors; fms-Like Tyrosine Kinase 3 - genetics; Gene Expression Regulation, Leukemic - drug effects; Glucocorticoids - pharmacology; Glucocorticoids - therapeutic use; Humans; Inflammation - genetics; Leukemia, Myeloid, Acute - drug therapy; Mice; Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Neoplasia; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplastic Stem Cells - drug effects; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Selection, Genetic; Transcriptome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019003124

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. •Treatment of FLT3 internal tandem duplication AML with FLT3 inhibitors results in upregulation of inflammatory pathways in DTPs.•Anti-inflammatory GCs in combination with FLT3 inhibitors decrease DTPs by upregulating BIM and downregulating MCL-1. [Display omitted]