title: A genomic approach to predict synergistic combinations for breast cancer treatment.
abstract: We leverage genomic and biochemical data to identify synergistic drug regimens for breast cancer. In order to study the mechanism of the histone deacetylase (HDAC) inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) in breast cancer, we generated and validated genomic profiles of drug response using a series of breast cancer cell lines sensitive to each drug. These genomic profiles were then used to model drug response in human breast tumors and show significant correlation between VPA and SAHA response profiles in multiple breast tumor data sets, highlighting their similar mechanism of action. The genes deregulated by VPA and SAHA converge on the cell cycle pathway (Bayes factor 5.21 and 5.94, respectively; P-value 10(-8.6) and 10(-9), respectively). In particular, VPA and SAHA upregulate key cyclin-dependent kinase (CDK) inhibitors. In two independent datasets, cancer cells treated with CDK inhibitors have similar gene expression profile changes to the cellular response to HDAC inhibitors. Together, these results led us to hypothesize that VPA and SAHA may interact synergistically with CDK inhibitors such as PD-033299. Experiments show that HDAC and CDK inhibitors have statistically significant synergy in both breast cancer cell lines and primary 3-dimensional cultures of cells from pleural effusions of patients. Therefore, synergistic relationships between HDAC and CDK inhibitors may provide an effective combinatorial regimen for breast cancer. Importantly, these studies provide an example of how genomic analysis of drug-response profiles can be used to design rational drug combinations for cancer treatment.
authors.affiliation: Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: R
authors.initials: R
authors.lastname: Soldi
authors.forename: A L
authors.initials: AL
authors.lastname: Cohen
authors.forename: L
authors.initials: L
authors.lastname: Cheng
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: P J
authors.initials: PJ
authors.lastname: Moos
authors.forename: A H
authors.initials: AH
authors.lastname: Bild
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics / Q000379:methods; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015854:Up-Regulation / Q000187:drug effects; D014635:Valproic Acid / Q000008:administration & dosage; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047428:Protein Kinase Inhibitors; D000077337:Vorinostat; D014635:Valproic Acid; D018844:Cyclin-Dependent Kinases
references.citation: Clin Cancer Res. 2004 Oct 15;10(20):6962-8
references.pmid: 15501975
references.citation: Clin Cancer Res. 2004 Feb 1;10(3):1141-9
references.pmid: 14871994
references.citation: Carcinogenesis. 2008 Mar;29(3):560-7
references.pmid: 18204075
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4389-94
references.pmid: 12677000
references.citation: Oncogene. 2002 Apr 18;21(17):2741-9
references.pmid: 11965547
references.citation: BMC Cancer. 2008 Mar 06;8:68
references.pmid: 18325103
references.citation: PLoS One. 2009;4(4):e5011
references.pmid: 19340297
references.citation: Int J Biochem Cell Biol. 2009 Jan;41(1):225-34
references.pmid: 18789398
references.citation: Ann Oncol. 2009 Jun;20(6):993-9
references.pmid: 19150946
references.citation: Mol Cell Biol. 2005 Dec;25(23):10220-34
references.pmid: 16287840
references.citation: Nat Rev Mol Cell Biol. 2006 Mar;7(3):211-24
references.pmid: 16496023
references.citation: Cancer Lett. 2008 Sep 28;269(1):7-17
references.pmid: 18462867
references.citation: Nat Rev Cancer. 2006 Feb;6(2):107-16
references.pmid: 16491070
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Cancer Res. 2009 Feb 1;69(3):958-66
references.pmid: 19176386
references.citation: Mol Cancer Ther. 2009 Sep;8(9):2517-25
references.pmid: 19755512
references.citation: Annu Rev Biochem. 2001;70:81-120
references.pmid: 11395403
references.citation: Int J Cancer. 2006 Dec 1;119(11):2546-56
references.pmid: 16988944
references.citation: Ann Oncol. 2007 Sep;18(9):1529-38
references.pmid: 17761710
references.citation: Novartis Found Symp. 2004;259:269-81; discussion 281-8
references.pmid: 15171260
references.citation: Nature. 2000 Aug 17;406(6797):747-52
references.pmid: 10963602
references.citation: Prostate. 2004 May 1;59(2):177-89
references.pmid: 15042618
references.citation: N Engl J Med. 2011 Mar 17;364(11):985-7
references.pmid: 21323535
references.citation: J Clin Oncol. 2007 May 20;25(15):1979-85
references.pmid: 17513804
references.citation: Eur J Biochem. 1997 Jan 15;243(1-2):527-36
references.pmid: 9030781
references.citation: Mol Cancer. 2006 Oct 06;5:44
references.pmid: 17026765
references.citation: PLoS One. 2009;4(2):e4482
references.pmid: 19221586
references.citation: Mol Cancer Ther. 2003 Feb;2(2):151-63
references.pmid: 12589032
references.citation: Physiol Genomics. 2005 Feb 10;20(3):233-43
references.pmid: 15598877
references.citation: Clin Cancer Res. 2009 Apr 1;15(7):2488-96
references.pmid: 19318486
references.citation: Cancer Cell. 2005 Jan;7(1):17-23
references.pmid: 15652746
references.citation: Expert Opin Investig Drugs. 2002 Dec;11(12):1695-713
references.pmid: 12457432
references.citation: PLoS One. 2006 Dec 20;1:e98
references.pmid: 17183730
references.citation: J Pharmacol Exp Ther. 2001 Sep;298(3):865-72
references.pmid: 11504778
references.citation: Mol Cancer Ther. 2004 Nov;3(11):1427-38
references.pmid: 15542782
references.citation: Genes Dev. 2004 Oct 1;18(19):2315-35
references.pmid: 15466484
references.citation: Breast Cancer Res Treat. 2005 Nov;94(1):11-6
references.pmid: 16172792
references.citation: Cancer Cell. 2006 Dec;10(6):515-27
references.pmid: 17157791
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14621-6
references.pmid: 20679242
references.citation: Anticancer Drugs. 2009 Sep;20(8):682-92
references.pmid: 19606018
references.citation: Cancer Cell Int. 2006 Jan 31;6:2
references.pmid: 16448574
references.citation: Cell Cycle. 2005 Apr;4(4):549-51
references.pmid: 15738652
references.citation: Science. 2006 Sep 29;313(5795):1929-35
references.pmid: 17008526
references.citation: J Biol Chem. 2006 May 12;281(19):13548-13558
references.pmid: 16533812