title: Targeting an Achilles' heel of cancer with a WRN helicase inhibitor.
abstract: Our recently published work suggests that DNA helicases such as the Werner syndrome helicase (WRN) represent a novel class of proteins to target for anticancer therapy. Specifically, pharmacological inhibition of WRN helicase activity in human cells defective in the Fanconi anemia (FA) pathway of interstrand cross-link (ICL) repair are sensitized to the DNA cross-linking agent and chemotherapy drug mitomycin C (MMC) by the WRN helicase inhibitor NSC 617145. (1) The mechanistic basis for the synergistic interaction between NSC 617145 and MMC is discussed in this paper and extrapolated to potential implications for genetic or chemically induced synthetic lethality provoked by cellular exposure to the WRN helicase inhibitor under the context of relevant DNA repair deficiencies associated with cancers or induced by small-molecule inhibitors. Experimental data are presented showing that small-molecule inhibition of WRN helicase elevates sensitivity to MMC-induced stress in human cells that are deficient in both FANCD2 and DNA protein kinase catalytic subunit (DNA-PKcs). These findings suggest a model in which drug-mediated inhibition of WRN helicase activity exacerbates the deleterious effects of MMC-induced DNA damage when both the FA and NHEJ pathways are defective. We conclude with a perspective for the FA pathway and synthetic lethality and implications for DNA repair helicase inhibitors that can be developed for anticancer strategies.
authors.affiliation: Laboratory of Molecular Gerontology; National Institute on Aging; National Institutes of Health; NIH Biomedical Research Center; Baltimore, MD USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Aggarwal
authors.forename: Taraswi
authors.initials: T
authors.lastname: Banerjee
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Sommers
authors.forename: Robert M
authors.initials: RM
authors.lastname: Brosh
mesh_terms: D002460:Cell Line; D059766:DNA End-Joining Repair / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005199:Fanconi Anemia / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D008301:Maleimides / Q000494:pharmacology; D016685:Mitomycin / Q000494:pharmacology; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology; D053484:RecQ Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D008301:Maleimides; C584579:NSC 617145; D016685:Mitomycin; D053484:RecQ Helicases
keywords: DNA repair; Fanconi anemia; Werner syndrome; anticancer therapy; helicase; small molecule; synthetic lethality
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10394-9
references.pmid: 17563354
references.citation: Aging (Albany NY). 2011 Mar;3(3):277-90
references.pmid: 21464516
references.citation: Nature. 2005 Apr 14;434(7035):913-7
references.pmid: 15829966
references.citation: Cell Cycle. 2011 Dec 1;10(23):4039-46
references.pmid: 22101264
references.citation: Mech Ageing Dev. 2010 Jun;131(6):436-44
references.pmid: 20600238
references.citation: Genes Dev. 2012 Jul 1;26(13):1393-408
references.pmid: 22751496
references.citation: Science. 2010 Jul 9;329(5988):219-23
references.pmid: 20538911
references.citation: Mol Cancer. 2009 Apr 16;8:24
references.pmid: 19371427
references.citation: J Biol Chem. 2005 Dec 9;280(49):40559-67
references.pmid: 16223718
references.citation: Blood. 2008 Aug 15;112(4):1413-23
references.pmid: 18524993
references.citation: Mol Cell Biol. 2002 Oct;22(20):6971-8
references.pmid: 12242278
references.citation: Aging Cell. 2003 Aug;2(4):191-9
references.pmid: 12934712
references.citation: Nat Rev Cancer. 2011 Jun 24;11(7):467-80
references.pmid: 21701511
references.citation: Cell Cycle. 2011 Apr 15;10(8):1192-9
references.pmid: 21487248
references.citation: Cell Cycle. 2009 Oct 1;8(19):3112-9
references.pmid: 19755856
references.citation: Nat Rev Cancer. 2013 Jul;13(7):443-54
references.pmid: 23760025
references.citation: Cell Cycle. 2012 Aug 15;11(16):3036-44
references.pmid: 22871734
references.citation: Mol Cell. 2010 Jul 30;39(2):164-6
references.pmid: 20670885
references.citation: Mol Cell. 2010 Jul 9;39(1):25-35
references.pmid: 20598602
references.citation: J Clin Invest. 2007 May;117(5):1440-9
references.pmid: 17431503
references.citation: Nature. 2005 Apr 14;434(7035):917-21
references.pmid: 15829967
references.citation: Genes Dev. 2000 Apr 15;14(8):907-12
references.pmid: 10783163
references.citation: Blood. 2006 Jun 1;107(11):4223-33
references.pmid: 16493006
references.citation: Nat Rev Cancer. 2012 Dec;12(12):801-17
references.pmid: 23175119
references.citation: FEBS J. 2010 Sep;277(17):3470-88
references.pmid: 20670277
references.citation: Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1525-30
references.pmid: 21220316
references.citation: Nature. 2013 Jan 17;493(7432):356-63
references.pmid: 23325218
references.citation: Aging (Albany NY). 2011 Mar;3(3):311-8
references.pmid: 21389352
references.citation: Cell Cycle. 2009 Jun 15;8(12):1872-6
references.pmid: 19440052
references.citation: Cell Cycle. 2008 Mar 15;7(6):796-807
references.pmid: 18250621
references.citation: Nucleic Acids Res. 2006 May 19;34(9):2751-60
references.pmid: 16714450
references.citation: Cancer Res. 2013 Sep 1;73(17):5497-507
references.pmid: 23867477
references.citation: Mol Cell. 2012 Apr 27;46(2):125-35
references.pmid: 22445484
references.citation: Anemia. 2012;2012:481583
references.pmid: 22693661
references.citation: Nat Rev Cancer. 2013 Aug;13(8):542-58
references.pmid: 23842644