Resistance to HSP90 inhibition involving loss of MCL1 addiction

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,...

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Bibliographic Details
Published in:Oncogene 2016-03, Vol.35 (12), p.1483-1492
Main Authors: Busacca, S, Law, E W P, 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, D A
Format: Article
Language:English
Subjects:
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Apoptosis
Cancer
Cell Biology
Cell Line, Tumor
Drug resistance
Gene expression
Genetic aspects
Health aspects
Heat shock proteins
HSP90 Heat-Shock Proteins - antagonists & inhibitors
Human Genetics
Humans
Innovations
Internal Medicine
Medicine
Medicine & Public Health
Molecular targeted therapy
Myeloid Cell Leukemia Sequence 1 Protein - genetics
Oncology
Original
original-article
Peptidomimetics
Properties
Signal transduction
STAT5 Transcription Factor - genetics
Tumor proteins
Tumor Suppressor Proteins - genetics
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Summary: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.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.213