Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/38106
Title: Resistance to HSP90 inhibition involving loss of MCL1 addiction
Authors: Busacca, S.
Law, E. W.
Powley, I. R.
Proia, D. A.
Sequeira, M.
Le Quesne, J.
Klabatsa, A.
Edwards, J. M.
Matchett, K. B.
Luo, J. L.
Pringle, J. H.
El-Tanani, M.
MacFarlane, M.
Fennell, Dean A.
First Published: 22-Jun-2015
Publisher: Nature Publishing Group
Citation: Oncogene, 2016, 35 (12), pp. 1483-1492
Abstract: Inhibition 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.
DOI Link: 10.1038/onc.2015.213
ISSN: 0950-9232
eISSN: 1476-5594
Links: http://www.nature.com/onc/journal/v35/n12/full/onc2015213a.html
http://hdl.handle.net/2381/38106
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2015. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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