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Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.

Published version
Peer-reviewed

Type

Article

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Authors

Zhang, Haijiao 
Savage, Samantha 
Schultz, Anna Reister 
Bottomly, Daniel 
White, Libbey 

Abstract

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

Description

Keywords

Adult, Aged, Aged, 80 and over, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Epigenesis, Genetic, Female, GTP Phosphohydrolases, HEK293 Cells, Humans, Inhibitory Concentration 50, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Male, Membrane Proteins, Mice, Middle Aged, Mutation, Piperidines, Protein Kinase Inhibitors, Pyridones, Pyrimidinones, Tandem Repeat Sequences, Treatment Outcome, Exome Sequencing, fms-Like Tyrosine Kinase 3

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

10

Publisher

Nature Communications
Sponsorship
This work was supported in part by The Leukemia & Lymphoma Society Beat AML Program, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research and the National Cancer Institute (1R01CA183947–01; 1U01CA217862–01; 1U54CA224019-01; 3P30CA069533-18S5). H.Z. received a Collins Medical Trust research grant. S.D.B. was supported by the National Cancer Institute (5R01CA138744-08).
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