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Resistance to HSP90 inhibition involving loss of MCL1 addiction

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posted on 2016-09-28, 14:56 authored by S. Busacca, E. W. Law, I. R. Powley, D. A. Proia, M. Sequeira, J. Le Quesne, A. Klabatsa, J. M. Edwards, K. B. Matchett, J. L. Luo, J. H. Pringle, M. El-Tanani, M. MacFarlane, Dean A. Fennell
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.

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Citation

Oncogene, 2016, 35 (12), pp. 1483-1492

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

  • VoR (Version of Record)

Published in

Oncogene

Publisher

Nature Publishing Group

issn

0950-9232

eissn

1476-5594

Acceptance date

2015-03-14

Copyright date

2015

Available date

2016-09-28

Publisher version

http://www.nature.com/onc/journal/v35/n12/full/onc2015213a.html

Language

en

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