Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.
View / Open Files
Authors
Zhang, Haijiao
Savage, Samantha
Schultz, Anna Reister
Bottomly, Daniel
White, Libbey
Segerdell, Erik
Wilmot, Beth
McWeeney, Shannon K
Eide, Christopher A
Nechiporuk, Tamilla
Carlos, Amy
Henson, Rachel
Lin, Chenwei
Searles, Robert
Ho, Hoang
Lam, Yee Ling
Sweat, Richard
Follit, Courtney
Jain, Vinay
Lind, Evan
Borthakur, Gautam
Garcia-Manero, Guillermo
Ravandi, Farhad
Kantarjian, Hagop M
Cortes, Jorge
Collins, Robert
Buelow, Daelynn R
Baker, Sharyn D
Druker, Brian J
Tyner, Jeffrey W
Publication Date
2019-01-16Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Nature Communications
Volume
10
Issue
1
Number
244
Pages
1-13
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Zhang, H., Savage, S., Schultz, A. R., Bottomly, D., White, L., Segerdell, E., Wilmot, B., et al. (2019). Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.. Nat Commun, 10 (1. 244), 1-13. https://doi.org/10.1038/s41467-018-08263-x
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.
Relationships
Is supplemented by: https://doi.org/10.1038/s41467-018-08263-x
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).
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-08263-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290380
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The following licence files are associated with this item: