Fatty Acid Oxidation Is an Adaptive Survival Pathway Induced in Prostate Tumors by HSP90 Inhibition.

Autor:	Nassar ZD; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.; Freemasons Foundation Centre for Men's Health, Adelaide, South Australia, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Mah CY; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.; Freemasons Foundation Centre for Men's Health, Adelaide, South Australia, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Centenera MM; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.; Freemasons Foundation Centre for Men's Health, Adelaide, South Australia, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Irani S; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Sadowski MC; Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia., Scott JS; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.; Freemasons Foundation Centre for Men's Health, Adelaide, South Australia, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Nguyen EV; Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Australia., Nagarajan SR; Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Moldovan M; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia., Lynn DJ; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.; College of Medicine and Public Health, Flinders University, Bedford Park, Adelaide, South Australia, Australia., Daly RJ; Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Australia., Hoy AJ; Discipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia., Butler LM; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia. lisa.butler@adelaide.edu.au.; Freemasons Foundation Centre for Men's Health, Adelaide, South Australia, Australia.; South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Jazyk:	angličtina
Zdroj:	Molecular cancer research : MCR [Mol Cancer Res] 2020 Oct; Vol. 18 (10), pp. 1500-1511. Date of Electronic Publication: 2020 Jul 15.
DOI:	10.1158/1541-7786.MCR-20-0570
Abstrakt:	HSP90 is a molecular chaperone required for stabilization 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. However, clinical use of HSP90 inhibitors for prostate cancer 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 (PDE) 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 prostate cancer 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 cotargeting this process will sensitize prostate cancer cells to HSP90 inhibition. Combination treatment of AUY922 with a clinical inhibitor of fatty acid oxidation, perhexiline, synergistically decreased viability of several prostate cancer 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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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