title: An evolutionarily conserved synthetic lethal interaction network identifies FEN1 as a broad-spectrum target for anticancer therapeutic development.
abstract: Harnessing genetic differences between cancerous and noncancerous cells offers a strategy for the development of new therapies. Extrapolating from yeast genetic interaction data, we used cultured human cells and siRNA to construct and evaluate a synthetic lethal interaction network comprised of chromosome instability (CIN) genes that are frequently mutated in colorectal cancer. A small number of genes in this network were found to have synthetic lethal interactions with a large number of cancer CIN genes; these genes are thus attractive targets for anticancer therapeutic development. The protein product of one highly connected gene, the flap endonuclease FEN1, was used as a target for small-molecule inhibitor screening using a newly developed fluorescence-based assay for enzyme activity. Thirteen initial hits identified through in vitro biochemical screening were tested in cells, and it was found that two compounds could selectively inhibit the proliferation of cultured cancer cells carrying inactivating mutations in CDC4, a gene frequently mutated in a variety of cancers. Inhibition of flap endonuclease activity was also found to recapitulate a genetic interaction between FEN1 and MRE11A, another gene frequently mutated in colorectal cancers, and to lead to increased endogenous DNA damage. These chemical-genetic interactions in mammalian cells validate evolutionarily conserved synthetic lethal interactions and demonstrate that a cross-species candidate gene approach is successful in identifying small-molecule inhibitors that prove effective in a cell-based cancer model.
authors: Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
authors: Derek M
authors: DM
authors: van Pel
authors: Irene J
authors: IJ
authors: Barrett
authors: Yoko
authors: Y
authors: Shimizu
authors: Babu V
authors: BV
authors: Sajesh
authors: Brent J
authors: BJ
authors: Guppy
authors: Tom
authors: T
authors: Pfeifer
authors: Kirk J
authors: KJ
authors: McManus
authors: Philip
authors: P
authors: Hieter
mesh_terms: D005075:Biological Evolution; D049109:Cell Proliferation; D043171:Chromosomal Instability; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D045585:Flap Endonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053263:Gene Regulatory Networks; D005804:Genes, Lethal; D005813:Genes, Synthetic; D006801:Humans; D000076228:MRE11 Homologue Protein; D058990:Molecular Targeted Therapy; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D045585:Flap Endonucleases; D000076228:MRE11 Homologue Protein; C468317:FEN1 protein, human
references: Nature. 2012 Mar 28;483(7391):603-7
references: 22460905
references: Nature. 1994 Sep 22;371(6495):346-7
references: 8090205
references: Nature. 1997 Apr 10;386(6625):623-7
references: 9121588
references: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references: 11259830
references: Cancer Res. 2004 May 1;64(9):2998-3001
references: 15126332
references: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3276-81
references: 19218431
references: Curr Opin Cell Biol. 2006 Dec;18(6):658-67
references: 17046232
references: Genetics. 2007 Dec;177(4):2525-30
references: 18073444
references: Nat Biotechnol. 2011 Apr;29(4):361-7
references: 21441928
references: Nucleic Acids Res. 2011 Feb;39(3):781-94
references: 20929870
references: PLoS One. 2011 Feb 02;6(2):e16691
references: 21311763
references: Science. 1997 Nov 7;278(5340):1064-8
references: 9353181
references: Cell. 2011 Oct 14;147(2):306-19
references: 22000011
references: Science. 2010 Jan 22;327(5964):425-31
references: 20093466
references: Cell Res. 2011 Jul;21(7):1052-67
references: 21383776
references: Nat Cell Biol. 2001 Aug;3(8):761-6
references: 11483963
references: Cell. 2011 Mar 4;144(5):646-74
references: 21376230
references: Nat Methods. 2008 Aug;5(8):711-8
references: 18622397
references: EMBO Rep. 2005 Jan;6(1):83-9
references: 15592449
references: PLoS Genet. 2012;8(3):e1002574
references: 22412391
references: Cancer Res. 2011 May 15;71(10):3447-52
references: 21270108
references: Nat Chem Biol. 2008 Feb;4(2):119-25
references: 18176557
references: Nucleic Acids Res. 2011 Jul;39(12):e82
references: 21493687
references: EMBO J. 1994 Mar 1;13(5):1235-46
references: 8131753
references: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3925-30
references: 17360454
references: Trends Cell Biol. 1999 Dec;9(12):M57-60
references: 10611684
references: Nucleic Acids Res. 2011 Apr;39(8):3166-75
references: 21183466
references: Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8
references: 18299561
references: Cancer Res. 2005 Dec 15;65(24):11361-6
references: 16357143
references: Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):686-91
references: 21148102
references: Oncology. 2009;76(6):430-4
references: 19420964
references: J Biol Chem. 2003 Apr 18;278(16):13728-39
references: 12554738
references: J Biol Chem. 2007 Feb 9;282(6):3465-77
references: 17138563
references: Nature. 2005 Apr 14;434(7035):917-21
references: 15829967
references: J Pathol. 2012 Jun;227(2):131-5
references: 22323043
references: Cell Oncol. 2010;32(5-6):347-59
references: 20448329
references: Bioorg Med Chem Lett. 2005 Jan 17;15(2):277-81
references: 15603939
references: Science. 2001 Dec 14;294(5550):2364-8
references: 11743205
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D502-7
references: 19880385
references: Nature. 2005 Apr 14;434(7035):913-7
references: 15829966
references: Mol Cell. 2004 Nov 5;16(3):487-96
references: 15525520
references: J Biol Chem. 2012 Jun 22;287(26):21980-91
references: 22570476
references: Nature. 2009 Apr 9;458(7239):776-9
references: 19169242
references: Methods Enzymol. 2010;470:145-79
references: 20946810
references: Nature. 2004 Mar 4;428(6978):77-81
references: 14999283
references: Cancer Res. 2007 Oct 1;67(19):9006-12
references: 17909001
references: Trends Biotechnol. 2010 Mar;28(3):134-41
references: 20015561
references: EMBO J. 1997 Jun 2;16(11):3341-8
references: 9214649
references: Nat Chem Biol. 2008 Aug;4(8):498-506
references: 18622389
references: Nat Genet. 2012 Dec;44(12):1310-5
references: 23104009
references: Oncogene. 1999 Jun 3;18(22):3422-6
references: 10362364
references: Science. 2004 Feb 6;303(5659):808-13
references: 14764870
references: Cancer Res. 2011 Mar 1;71(5):1858-70
references: 21363922
references: Nature. 1998 Mar 19;392(6673):300-3
references: 9521327
references: J Cell Biol. 2001 Apr 30;153(3):613-20
references: 11331310
references: J Biol Chem. 1996 Oct 18;271(42):25888-97
references: 8824221
references: Nat Chem Biol. 2011 Apr 13;7(7):428-30
references: 21490603
references: Mol Cell Biol. 2001 Mar;21(5):1719-29
references: 11238909
references: Nature. 2012 Mar 28;483(7391):570-5
references: 22460902
references: Int J Radiat Biol. 2007 May;83(5):319-29
references: 17457757
references: EMBO Mol Med. 2009 Sep;1(6-7):315-22
references: 20049735
references: Cancer Res. 2012 Jun 1;72(11):2814-21
references: 22447567
references: Science. 1997 Jan 17;275(5298):343-9
references: 8994024
references: Nat Rev Mol Cell Biol. 2011 Feb;12(2):90-103
references: 21252998
references: Mol Biol Cell. 2009 Dec;20(24):5306-13
references: 19846659
references: Cancer Cell. 2010 Mar 16;17(3):235-48
references: 20227038
references: J Biol Chem. 1998 Apr 10;273(15):8842-8
references: 9535864
references: PLoS Genet. 2011 Apr;7(4):e1002057
references: 21552543
references: Mutat Res. 2010 Jan 5;683(1-2):1-8
references: 19800897