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dc.contributor.authorSmith, AM
dc.contributor.authorZhang, CRC
dc.contributor.authorCristino, Alexandre
dc.contributor.authorGrady, JP
dc.contributor.authorFink, JL
dc.contributor.authorMoore, AS
dc.date.accessioned2020-02-17T01:22:20Z
dc.date.available2020-02-17T01:22:20Z
dc.date.issued2019
dc.identifier.issn1949-2553
dc.identifier.doi10.18632/oncotarget.27206
dc.identifier.urihttp://hdl.handle.net/10072/391549
dc.description.abstractKinases such as MEK are attractive targets for novel therapy in cancer, including acute myeloid leukaemia (AML). Acquired and inherent resistance to kinase inhibitors, however, is becoming an increasingly important challenge for the clinical success of such therapeutics, and often arises from mutations in the drug-binding domain of the target kinase. To identify possible causes of resistance to MEK inhibition, we generated a model of resistance by long-term treatment of AML cells with AZD6244 (selumetinib). Remarkably, resistance to MEK inhibition was due to acquired PTEN haploinsufficiency, rather than mutation of MEK. Resistance via this mechanism was confirmed using CRISPR/Cas9 technology targeting exon 5 of PTEN. While PTEN loss has been previously implicated in resistance to a number of other therapeutic agents, this is the first time that it has been shown directly and in AML.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherImpact Journals
dc.relation.ispartofpagefrom5755
dc.relation.ispartofpageto5767
dc.relation.ispartofissue56
dc.relation.ispartofjournalOncotarget
dc.relation.ispartofvolume10
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchCancer cell biology
dc.subject.fieldofresearchcode3211
dc.subject.fieldofresearchcode321101
dc.titlePTEN deletion drives acute myeloid leukaemia resistance to MEK inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationSmith, AM; Zhang, CRC; Cristino, A; Grady, JP; Fink, JL; Moore, AS, PTEN deletion drives acute myeloid leukaemia resistance to MEK inhibitors, Oncotarget, 2019, 10 (56), pp. 5755-5767
dcterms.licensehttp://creativecommons.org/licenses/by/3.0/
dc.date.updated2020-02-17T01:18:20Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2019 Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
gro.hasfulltextFull Text
gro.griffith.authorCristino, Alex


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