Synthetic lethality as a functional tool in basic research and in anticancer therapy

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Synthetic lethality as a functional tool in basic research and in anticancer therapy

Monika Toma 1 , Tomasz Skorski 2 , Tomasz Śliwiński 1

1. Katedra Genetyki Molekularnej Uniwersytetu Łódzkiego
2. Department of Microbiology and Immunology, and Fels Institute for Cancer Research, Temple University, School of Medicine, Philadelphia, PA, USA

Published: 2014-09-03
DOI: 10.5604/17322693.1119792
GICID: 01.3001.0003.1284
Available language versions: en pl
Issue: Postepy Hig Med Dosw 2014; 68 : 1091-1103

 

Abstract

Nowadays, cancer and anticancer therapy are increasingly mentioned topics. Groups of researchers keep looking for a tool that will specifically and efficiently eliminate abnormal cells without any harm for the normal ones. Such method entails the reduction of therapy’s side effects, thus also improving patient’s recovery. Discovery of synthetic lethality has become a new hope to create effective, personalized therapy of cancer. Researchers noted that pairs of simultaneously mutated genes can lead to cell death, whereas each gene from that pair mutated individually does not result in cell lethality. Cancer cells accumulate numerous changes in their genetic material. By defining the pairs of genes interacting in cell pathways we are able to identify a potential anticancer therapy. It is believed that such a process has evolved to create cell resistance for a single gene mutation. Proper functioning of a pathway is not dependent on a single gene. Such a solution, however, also led to the evolution of multifactorial diseases such as cancer. Research techniques using iRNA, shRNA or small molecule libraries allow us to find genes that are connected in synthetic lethality interactions. Synthetic lethality may be applied not only as an anticancer therapy but also as a tool for identifying the functions of recently recognized genes. In addition, studying synthetic lethality broadens our understanding of the molecular mechanisms governing cancer cells, which should be helpful in designing highly effective personalized cancer therapies.

References

  • 1. Adams P.D., Kaelin W.G. Jr.: The cellular effects of E2F overexpression.Curr. Top. Microbiol. Immunol., 1996; 208: 79-93
    Google Scholar
  • 2. Barbour L., Xiao W.: Synthetic lethal screen. Methods Mol. Biol.,2006; 313: 161-169
    Google Scholar
  • 3. Berthet C, Aleem E., Coppola V., Tessarollo L., Kaldis P.: Cdk2knockout mice are viable. Curr. Biol., 2003; 13: 1775-1785
    Google Scholar
  • 4. Bridges C.B.: The origin of variations in sexual and sex-limitedcharacters. Am. Nat., 1922; 56: 51-63
    Google Scholar
  • 5. Bryant H.E., Schultz N., Thomas H.D., Parker K.M., Flower D., LopezE., Kyle S., Meuth M., Curtin N.J., Helleday T.: Specific killing ofBRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature, 2005; 434: 913-917
    Google Scholar
  • 6. Buchdunger E., Cioffi C.L., Law N., Stover D., Ohno-Jones S., DrukerB.J., Lydon N.B.: Abl protein-tyrosine kinase inhibitor STI571 inhibitsin vitro signal transduction mediated by c-kit and platelet-derivedgrowth factor receptors. J. Pharmacol. Exp. Ther., 2000; 295: 139-145
    Google Scholar
  • 7. Chan D.A., Giaccia A.J.: Harnessing synthetic lethal interactions inanticancer drug discovery. Nat. Rev. Drug Discov., 2011; 10: 351-364
    Google Scholar
  • 8. Chan D.A., Giaccia A.J.: Targeting cancer cells by synthetic lethality:autophagy and VHL in cancer therapeutics. Cell Cycle, 2008; 7:2987-2990
    Google Scholar
  • 9. Cohen M.H., Williams G., Johnson J.R., Duan J., Gobburu J., GobburuJ., Rahman A., Benson K., Leighton J., Kim S.K., Wood R., RothmannM., Chen G., U K.M., Staten A.M., Pazdur R.: Approval summaryfor imatinib mesylate capsules in the treatment of chronic myelogenousleukemia. Clin. Cancer Res., 2002; 8: 935-942
    Google Scholar
  • 10. Cramer-Morales K., Nieborowska-Skorska M., Scheibner K.,Padget M., Irvine D.A., Sliwinski T., Haas K., Lee J., Geng H., RoyD., Slupianek A., Rassool F.V., Wasik M.A., Childers W., Copland M.,Müschen M., Civin C.I., Skorski T.: Personalized synthetic lethalityinduced by targeting RAD52 in leukemias identified by gene mutationand expression profile. Blood, 2013; 122: 1293-1304
    Google Scholar
  • 11. Davierwala A.P., Haynes J., Li Z., Brost R.L., Robinson M.D., YuL., Mnaimneh S., Ding H., Zhu H., Chen Y., Cheng X., Brown G.W.,Boone C., Andrews B.J., Hughes T.R.: The synthetic genetic interactionspectrum of essential genes. Nat. Genet., 2005; 37: 1147-1152
    Google Scholar
  • 12. Davies A.A., Masson J.Y., McIlwraith M.J., Stasiak A.Z., Stasiak A.,Venkitaraman A.R., West S.C.: Role of BRCA2 in control of the RAD51recombination and DNA repair protein. Mol. Cell, 2001; 7: 273-282
    Google Scholar
  • 13. Dixon S.J., Fedyshyn Y., Koh J.L., Prasad T.S., Chahwan C., ChuaG., Toufighi K., Baryshnikova A., Hayles J., Hoe K.L., Kim D.U., ParkH.O., Myers C.L., Pandey A., Durocher D., Andrews B.J., Boone C.:Significant conservation of synthetic lethal genetic interaction networksbetween distantly related eukaryotes. Proc. Natl. Acad. Sci.USA, 2008; 105: 16653-16658
    Google Scholar
  • 14. Dobzhansky T.H.: Genetics of natural populations. XIII. Recombinationand variability in populations of Drosophila pseudoobscura.Genetics, 1946; 31: 269-290
    Google Scholar
  • 15. Dziewit Ł., Bartosik D.: Genomy prokariotyczne w świetle analizgenomicznych. Postępy Mikrobiol., 2011; 50: 87-96
    Google Scholar
  • 16. Farmer H., McCabe N., Lord C.J., Tutt A.N., Johnson D.A., RichardsonT.B., Santarosa M., Dillon K.J., Hickson I., Knights C., MartinN.M., Jackson S.P., Smith G.C., Ashworth A.: Targeting the DNA repairdefect in BRCA mutant cells as a therapeutic strategy. Nature,2005; 434: 917-921
    Google Scholar
  • 17. Feng Z., Scott S.P., Bussen W., Sharma G.G., Guo G., Pandita T.K.,Powell S.N.: Rad52 inactivation is synthetically lethal with BRCA2deficiency. Proc. Natl. Acad. Sci. USA, 2011; 108: 686-691
    Google Scholar
  • 18. Hartwell L.H., Szankasi P., Roberts C.J., Murray A.W., Friend S.H.:Integrating genetic approaches into the discovery of anticancerdrugs. Science, 1997; 278: 1064-1068
    Google Scholar
  • 19. Hutchinson L.: Targeted therapies: PARP inhibitor olaparib issafe and effective in patients with BRCA1 and BRCA2 mutations. Nat.Rev. Clin. Oncol., 2010; 7: 549
    Google Scholar
  • 20. Kaelin W.G. Jr.: The concept of synthetic lethality in the contextof anticancer therapy. Nat. Rev. Cancer, 2005; 5: 689-698
    Google Scholar
  • 21. Kamb A.: Consequences of nonadaptive alterations in cancer.Mol. Biol. Cell, 2003; 14: 2201-2205
    Google Scholar
  • 22. Kranz D., Boutros M.: A synthetic lethal screen identifies FAT1 as anantagonist of caspase-8 in extrinsic apoptosis. EMBO J., 2014; 33: 181-197
    Google Scholar
  • 23. Krek W., Xu G., Livingston D.M.: Cyclin A-kinase regulation ofE2F-1 DNA binding function underlies suppression of an S phasecheckpoint. Cell, 1995; 83: 1149-1158
    Google Scholar
  • 24. Luo J., Emanuele M.J., Li D., Creighton C.J., Schlabach M.R., WestbrookT.F., Wong K.K., Elledge S.J.: A genome-wide RNAi screenidentifies multiple synthetic lethal interactions with the Ras oncogene.Cell, 2009; 137: 835-848
    Google Scholar
  • 25. Martin S.A., Hewish M., Sims D., Lord C.J., Asworth A.: Parallelhigh-throughput RNA interference screens identify PINK1 as a potentialtherapeutic target for the treatment of DNA mismatch repairdeficientcancers. Cancer Res., 2011; 71: 1836-1848
    Google Scholar
  • 26. Martin S.A., McCabe N., Mullarkey M., Cummins R., Burgess D.J.,Nakabeppu Y., Oka S., Kay E., Lord C.J., Ashworth A.: DNA polymerasesas potential therapeutic targets for cancers deficient in the DNA mismatchrepair proteins MSH2 or MLH1. Cancer Cell, 2010; 17: 235-248
    Google Scholar
  • 27. Matsuda S., Kitagishi Y., Kobayashi M.: Function and characteristicsof PINK1 in mitochondria. Oxid. Med. Cell. Longev., 2013;2013: ID 601587
    Google Scholar
  • 28. McLellan J., O’Neil N., Tarailo S., Stoepel J., Bryan J., Rose A., HieterP.: Synthetic lethal genetic interactions that decrease somatic cell proliferationin Caenorhabditis elegans identify the alternative RFCCTF18as a candidate cancer drug target. Mol. Biol. Cell, 2009; 20: 5306-5313
    Google Scholar
  • 29. Mendes-Pereira A.M., Martin S.A., Brough R., McCarthy A., TaylorJ.R., Kim J.S., Waldman T., Lord C.J., Ashworth A.: Synthetic lethaltargeting of PTEN mutant cells with PARP inhibitors. EMBO Mol.Med., 2009; 1: 315-322
    Google Scholar
  • 30. Milosevic N., Kühnemuth B., Mühlberg L., Ripka S., GriesmannH., Lölkes C., Buchholz M., Aust D., Pilarsky C., Krug S., Gress T.,Michl P.: Synthetic lethality screen identifies RPS6KA2 as modifierof epidermal growth factor receptor activity in pancreatic cancer.Neoplasia, 2013; 15: 1354-1362
    Google Scholar
  • 31. Minami D., Takigawa N., Takeda H., Takata M., Ochi N., IchiharaE., Hisamoto A., Hotta K., Tanimoto M., Kiura K.: Synergistic effectof olaparib with combination of cisplatin on PTEN-deficient lungcancer cells. Mol. Cancer Res., 2013; 11: 140-148
    Google Scholar
  • 32. Neshat M.S., Mellinghoff I.K., Tran C., Stiles B., Thomas G., PetersenR., Frost P., Gibbons J.J., Wu H., Sawyers C.L.: Enhanced sensitivityof PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc.Natl. Acad. Sci. USA, 2001; 98: 10314-10319
    Google Scholar
  • 33. Nghiem P., Park P.K., Kim Y., Vaziri C., Schreiber S.L.: ATR inhibitionselectively sensitizes G1 checkpoint-deficient cells to lethalpremature chromatin condensation. Proc. Natl. Acad. Sci. USA, 2001;98: 9092-9097
    Google Scholar
  • 34. Ngo V.N., Davis R.E., Lamy L., Yu X., Zhao H., Lenz G., Lam L.T.,Dave S., Yang L., Powell J., Staudt L.M.: A loss-of-function RNA interferencescreen for molecular targets in cancer. Nature, 2006;441: 106-110
    Google Scholar
  • 35. Ooi S.L., Shoemaker D.D., Boeke J.D.: DNA helicase gene interactionnetwork defined using synthetic lethality analyzed by microarray.Nat. Genet., 2003; 35: 277-286
    Google Scholar
  • 36. Plummer R., Lorigan P., Steven N., Scott L., Middleton M.R.,Wilson R.H., Mulligan E., Curtin N., Wang D., Dewji R., Abbattista A.,Gallo J., Calvert H.: A phase II study of the potent PARP inhibitor,Rucaparib (PF-01367338, AG014699), with temozolomide in patientswith metastatic melanoma demonstrating evidence of chemopotentiation.Cancer Chemother. Pharmacol., 2013; 71: 1191-1199
    Google Scholar
  • 37. Queitsch C., Sangster T.A., Lindquist S.: Hsp90 as a capacitor ofphenotypic variation. Nature, 2002; 417: 618-624
    Google Scholar
  • 38. Roguev A., Bandyopadhyay S., Zofall M., Zhang K., Fischer T.,Collins S.R., Qu H., Shales M., Park H.O., Hayles J., Hoe K.L., Kim D.U.,Ideker T., Grewal S.I., Weissman J.S., Krogan N.J.: Conservation andrewiring of functional modules revealed by an epistasis map in fissionyeast. Science, 2008; 322: 405-410
    Google Scholar
  • 39. Simons A., Dafni N., Dotan I., Oron Y., Canaani D.: Establishmentof a chemical synthetic lethality screen in cultured human cells.Genome Res., 2001; 11: 266-273
    Google Scholar
  • 40. Tarailo M., Tarailo S., Rose A.M.: Synthetic lethal interactionsidentify phenotypic ‚’interologs’’ of the spindle assembly checkpointcomponents. Genetics, 2007; 177: 2525-2530
    Google Scholar
  • 41. Waldmann T.A.: Immunotherapy: past, present and future. Nat.Med., 2003; 9: 269-277
    Google Scholar
  • 42. Weinstein I.B., Joe A.K.: Mechanisms of disease: Oncogene addiction- a rationale for molecular targeting in cancer therapy. Nat.Clin. Pract. Oncol., 2006; 3: 448-457
    Google Scholar
  • 43. Wong S.L., Zhang L.V., Tong A.H., Li Z., Goldberg D.S., King O.D.,Lesage G., Vidal M., Andrews B., Bussey H., Boone C., Roth F.P.: Combiningbiological networks to predict genetic interactions. Proc. Natl.Acad. Sci. USA, 2004; 101: 15682-15687
    Google Scholar

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