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Nat Commun. 2019 Jan 16;10(1):244. doi: 10.1038/s41467-018-08263-x.

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

Author information

1
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
2
Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
3
Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
4
Howard Hughes Medical Institute, Portland, 97239, OR, USA.
5
Integrated Genomics, Knight Cancer Institute, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
6
AROG Pharmaceuticals, Dallas, 75240, TX, USA.
7
Molecular Microbiology & Immunology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA.
8
The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA.
9
University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA.
10
The Ohio State University College of Pharmacy and Comprehensive Cancer Center, Columbus, 43210, OH, USA.
11
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA. tynerj@ohsu.edu.
12
Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, 97239, OR, USA. tynerj@ohsu.edu.

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.

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