Fatty acid oxidation is an adaptive survival pathway induced in prostate tumors by heat shock protein 90 inhibition

Simple item page
dc.contributor.authorNassar, Z.D.
dc.contributor.authorMah, C.Y.
dc.contributor.authorCentenera, M.M.
dc.contributor.authorIrani, S.
dc.contributor.authorSadowski, M.C.
dc.contributor.authorScott, J.S.
dc.contributor.authorNguyen, E.V.
dc.contributor.authorNagarajan, S.R.
dc.contributor.authorMoldovan, M.
dc.contributor.authorLynn, D.J.
dc.contributor.authorDaly, R.J.
dc.contributor.authorHoy, A.J.
dc.contributor.authorButler, L.M.
dc.date.issued2020
dc.description.abstractHSP90 is a molecular chaperone required for stabilisation and activation of hundreds of client proteins, including many known oncoproteins. AUY922 (luminespib), a new generation HSP90 inhibitor, exhibits potent preclinical efficacy against several cancer types including prostate cancer (PCa). However, clinical use of HSP90 inhibitors for PCa has been limited by toxicity and treatment resistance. Here, we aimed to design an effective combinatorial therapeutic regimen that utilizes subtoxic doses of AUY922, by identifying potential survival pathways induced by AUY922 in clinical prostate tumors. We conducted a proteomic analysis of 30 patient-derived explants (PDEs) cultured in the absence and presence of AUY922, using quantitative mass spectrometry. AUY922 significantly increased the abundance of proteins involved in oxidative phosphorylation and fatty acid metabolism in the PDEs. Consistent with these findings, AUY922-treated PCa cell lines exhibited increased mitochondrial mass and activated fatty acid metabolism processes. We hypothesized that activation of fatty acid oxidation is a potential adaptive response to AUY922 treatment and that co-targeting this process will sensitize PCa cells to HSP90 inhibition. Combination treatment of AUY922 with a clinical inhibitor of fatty acid oxidation, perhexiline, synergistically decreased viability of several PCa cell lines, and had significant efficacy in PDEs. The novel drug combination treatment induced cell cycle arrest and apoptosis, and attenuated the heat shock response, a known mediator of HSP90 treatment resistance. This combination warrants further preclinical and clinical investigation as a novel strategy to overcome resistance to HSP90 inhibition. Implications: Metabolic pathways induced in tumor cells by therapeutic agents may be critical but targetable mediators of treatment resistance.
dc.description.statementofresponsibilityZeyad D. Nassar, Chui Yan Mah, Margaret M. Centenera, Swati Irani, Martin C. Sadowski, Julia S. Scott ... et al.
dc.identifier.citationMolecular Cancer Research, 2020; 18(10):1500-1511
dc.identifier.doi10.1158/1541-7786.mcr-20-0570
dc.identifier.issn1541-7786
dc.identifier.issn1557-3125
dc.identifier.orcidNassar, Z.D. [0000-0002-7779-2697]
dc.identifier.orcidMah, C.Y. [0000-0002-8820-4037]
dc.identifier.orcidCentenera, M.M. [0000-0002-2206-0632]
dc.identifier.orcidScott, J.S. [0000-0003-0022-0305]
dc.identifier.orcidMoldovan, M. [0000-0001-9680-8474]
dc.identifier.orcidButler, L.M. [0000-0003-2698-3220]
dc.identifier.urihttp://hdl.handle.net/2440/129273
dc.language.isoen
dc.publisherAmerican Association for Cancer Research
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1138648
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1058540
dc.relation.granthttp://purl.org/au-research/grants/arc/130101004
dc.rights© 2020 American Association for Cancer Research.
dc.source.urihttps://doi.org/10.1158/1541-7786.mcr-20-0570
dc.subjectHumans
dc.subjectProstatic Neoplasms
dc.subjectFatty Acids
dc.subjectSurvival Analysis
dc.subjectOxidation-Reduction
dc.subjectMale
dc.subjectHSP90 Heat-Shock Proteins
dc.subjectMass Spectrometry
dc.titleFatty acid oxidation is an adaptive survival pathway induced in prostate tumors by heat shock protein 90 inhibition
dc.typeJournal article
pubs.publication-statusPublished

Files

Collections

Medicine publications