title: Resistance to HSP90 inhibition involving loss of MCL1 addiction.
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.
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
authors.forename: S
authors.initials: S
authors.lastname: Busacca
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
authors.forename: E W P
authors.initials: EW
authors.lastname: Law
authors.affiliation: MRC Toxicology Unit, Leicester, UK.
authors.forename: I R
authors.initials: IR
authors.lastname: Powley
authors.affiliation: Synta Pharmaceuticals Corp., Lexington, MA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: Synta Pharmaceuticals Corp., Lexington, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sequeira
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.|MRC Toxicology Unit, Leicester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Le Quesne
authors.affiliation: Division of Cancer Studies, King's College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Klabatsa
authors.affiliation: MRC Toxicology Unit, Leicester, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Edwards
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
authors.forename: K B
authors.initials: KB
authors.lastname: Matchett
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
authors.forename: J L
authors.initials: JL
authors.lastname: Luo
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Pringle
authors.affiliation: Institute of Cancer Therapeutics, School of Life Sciences, University of Bradford, Bradford, UK.
authors.forename: M
authors.initials: M
authors.lastname: El-Tanani
authors.affiliation: MRC Toxicology Unit, Leicester, UK.
authors.forename: M
authors.initials: M
authors.lastname: MacFarlane
authors.affiliation: Department of Cancer Studies, Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Fennell
mesh_terms: D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D057786:Peptidomimetics; D050799:STAT5 Transcription Factor / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018841:HSP90 Heat-Shock Proteins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D057786:Peptidomimetics; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins