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dc.contributor.authorBusacca, S.*
dc.contributor.authorLaw, E.W.P.*
dc.contributor.authorPowley, I.R.*
dc.contributor.authorProia, D.A.*
dc.contributor.authorSequeira, M.*
dc.contributor.authorLe Quesne, J.*
dc.contributor.authorKlabatsa, A.*
dc.contributor.authorEdwards, J.M.*
dc.contributor.authorMatchett, K.B.*
dc.contributor.authorLuo, J.L.*
dc.contributor.authorPringle, J.H.*
dc.contributor.authorEl-Tanani, Mohamed*
dc.contributor.authorMacFarlane, M.*
dc.contributor.authorFennell, D.A.*
dc.date.accessioned2016-05-24T11:39:37Z
dc.date.available2016-05-24T11:39:37Z
dc.date.issued2016
dc.identifier.citationBusacca S, Law EWP, Powley IR et al. (2016) Resistance to HSP90 inhibition involving loss of MCL1 addiction. Oncogene. 35: 1483-1492.en_US
dc.identifier.urihttp://hdl.handle.net/10454/8406
dc.descriptionYesen_US
dc.description.abstractInhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttp://dx.doi.org/10.1038/onc.2015.213en_US
dc.rights© 2016 Nature. Reproduced in accordance with the publisher's self-archiving policy. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en_US
dc.subjectHeat-shock protein 90 (HSP90); HSP90 inhibition; Apoptosis; MCL1en_US
dc.titleResistance to HSP90 inhibition involving loss of MCL1 addictionen_US
dc.status.refereedYesen_US
dc.date.Accepted2015-03-14
dc.date.application2015-06-22
dc.typeArticleen_US
dc.type.versionpublished version paperen_US
refterms.dateFOA2018-07-25T14:00:39Z


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