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dc.contributor.authorZhang, Haijiao
dc.contributor.authorSavage, Samantha
dc.contributor.authorSchultz, Anna Reister
dc.contributor.authorBottomly, Daniel
dc.contributor.authorWhite, Libbey
dc.contributor.authorSegerdell, Erik
dc.contributor.authorWilmot, Beth
dc.contributor.authorMcWeeney, Shannon K
dc.contributor.authorEide, Christopher A
dc.contributor.authorNechiporuk, Tamilla
dc.contributor.authorCarlos, Amy
dc.contributor.authorHenson, Rachel
dc.contributor.authorLin, Chenwei
dc.contributor.authorSearles, Robert
dc.contributor.authorHo, Hoang
dc.contributor.authorLam, Yee Ling
dc.contributor.authorSweat, Richard
dc.contributor.authorFollit, Courtney
dc.contributor.authorJain, Vinay
dc.contributor.authorLind, Evan
dc.contributor.authorBorthakur, Gautam
dc.contributor.authorGarcia-Manero, Guillermo
dc.contributor.authorRavandi, Farhad
dc.contributor.authorKantarjian, Hagop M
dc.contributor.authorCortes, Jorge
dc.contributor.authorCollins, Robert
dc.contributor.authorBuelow, Daelynn R
dc.contributor.authorBaker, Sharyn D
dc.contributor.authorDruker, Brian J
dc.contributor.authorTyner, Jeffrey W
dc.date.accessioned2019-03-08T10:58:34Z
dc.date.available2019-03-08T10:58:34Z
dc.date.issued2019-01-16
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290380
dc.description.abstractFLT3 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.
dc.description.sponsorshipThis 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).
dc.languageeng
dc.language.isoen
dc.publisherNature Communications
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleClinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms.
dc.typeArticle
prism.endingPage13
prism.issueIdentifier1
prism.number244
prism.publicationDate2019
prism.publicationNameNat Commun
prism.startingPage1
prism.volume10
dc.identifier.doi10.17863/CAM.37610
pubs.declined2019-03-07T09:29:16.199+0000
dcterms.dateAccepted2018-12-21
rioxxterms.versionofrecord10.1038/s41467-018-08263-x
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2019-01-16
dc.contributor.orcidHenson, Richard [0000-0002-0712-2639]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
cam.issuedOnline2019-01-16
datacite.issupplementedby.doi10.1038/s41467-018-08263-x


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International