Skip to content
2000
Volume 25, Issue 15
  • ISSN: 1568-0266
  • E-ISSN: 1873-4294

Abstract

Synthetic lethality represents a novel paradigm in molecular targeted cancer therapy. In synthetic lethality, perturbation of one gene alone does not hinder cell viability, yet simultaneous perturbation of both genes results in a loss of cellular viability. The presence of gene mutations in cancer cells, as opposed to normal cells, provides an opportunity for targeted therapies that mimic the effects of the second genetic mutation, enabling selective eradication of cancer cells. Recent advances in high-throughput screening technologies, such as CRISPR-Cas9 and RNA interference, have significantly enhanced the identification of synthetic lethal interactions, expanding the potential targets for therapeutic intervention. Challenges in exploiting synthetic lethality for cancer treatment include the complexities of tumor biology, limited comprehension of synthetic lethal interactions, drug resistance, and impediments in screening and clinical translation. Emerging strategies, such as combination therapies and novel drug designs, are being developed to overcome these obstacles. By virtue of its selective lethality towards cancer cells bearing specific genetic alterations, targeting synthetic lethal genes holds the promise to provide wider therapeutic windows compared to traditional cytotoxic chemotherapy. This review describes the current state of synthetic lethality applications in cancer treatment, encompassing both biological and methodological perspectives. It highlights the latest advancements in synthetic lethality with emerging interventional strategies. Furthermore, it explores future directions for research and clinical implementation, aiming to refine and expand the therapeutic potential of synthetic lethality in oncology.

Loading

Article metrics loading...

/content/journals/ctmc/10.2174/0115680266349547241231051447
2025-01-30
2025-11-07
Loading full text...

Full text loading...

References

  1. SiegelR.L. GiaquintoA.N. JemalA. Cancer statistics, 2024.CA Cancer J. Clin.2024741124910.3322/caac.21820 38230766
    [Google Scholar]
  2. RaviS. AlencarA.M.Jr ArakelyanJ. XuW. StauberR. WangC.I. PapyanR. GhazaryanN. PereiraR.M. An update to hallmarks of cancer.Cureus2022145e24803e24803 35686268
    [Google Scholar]
  3. CortesJ. GarcíaP.J.M. CussacL.A. CuriglianoG. SaghirE.N.S. CardosoF. BarriosC.H. WagleS. RomanJ. HarbeckN. EniuA. KaufmanP.A. TaberneroJ. EstévezG.L. SchmidP. ArribasJ. Enhancing global access to cancer medicines.CA Cancer J. Clin.202070210512410.3322/caac.21597 32068901
    [Google Scholar]
  4. HanahanD. Hallmarks of cancer: New dimensions.Cancer Discov.2022121314610.1158/2159‑8290.CD‑21‑1059 35022204
    [Google Scholar]
  5. WangS. YangT. ShenA. QiangW. ZhaoZ. ZhangF. The scalp cooling therapy for hair loss in breast cancer patients undergoing chemotherapy: A systematic review and meta-analysis.Support. Care Cancer202129116943695610.1007/s00520‑021‑06188‑8 33847828
    [Google Scholar]
  6. HensonL.A. MaddocksM. EvansC. DavidsonM. HicksS. HigginsonI.J. Palliative care and the management of common distressing symptoms in advanced cancer: Pain, breathlessness, nausea and vomiting, and fatigue.J. Clin. Oncol.202038990591410.1200/JCO.19.00470 32023162
    [Google Scholar]
  7. PassaroA. BrahmerJ. AntoniaS. MokT. PetersS. Managing resistance to immune checkpoint inhibitors in lung cancer: Treatment and novel strategies.J. Clin. Oncol.202240659861010.1200/JCO.21.01845 34985992
    [Google Scholar]
  8. DrukerB.J. Perspectives on the development of a molecularly targeted agent.Cancer Cell200211313610.1016/S1535‑6108(02)00025‑9 12086885
    [Google Scholar]
  9. MalikN. YanH. YangH.H. AyazG. DuBoisW. TsengY.C. KimY.I. JiangS. LiuC. LeeM. HuangJ. CBFB cooperates with p53 to maintain TAp73 expression and suppress breast cancer.PLoS Genet.2021175e100955310.1371/journal.pgen.1009553 33945523
    [Google Scholar]
  10. HeX. LiuX. ZuoF. ShiH. JingJ. Artificial intelligence-based multi-omics analysis fuels cancer precision medicine.Semin. Cancer Biol.20238818720010.1016/j.semcancer.2022.12.009 36596352
    [Google Scholar]
  11. ImperialR. NazerM. AhmedZ. KamA.E. PluardT.J. BahajW. LevyM. KuzelT.M. HaydenD.M. PappasS.G. SubramanianJ. MasoodA. Matched whole-genome sequencing (wgs) and whole-exome sequencing (wes) of tumor tissue with circulating tumor dna (ctdna) analysis: Complementary modalities in clinical practice.Cancers (Basel)2019119139910.3390/cancers11091399 31546879
    [Google Scholar]
  12. ChenX. YangW. RobertsC.W.M. ZhangJ. Developmental origins shape the paediatric cancer genome.Nat. Rev. Cancer202424638239810.1038/s41568‑024‑00684‑9 38698126
    [Google Scholar]
  13. BedairiaN. MorinetF. MartyM. [Cancerology: Targets and targeted treatments].Pathol. Biol.201260421521610.1016/j.patbio.2012.05.005 22738994
    [Google Scholar]
  14. ChungE.K. YongS.H. LeeE.H. KimE.Y. ChangY.S. LeeS.H. New targeted therapy for non-small cell lung cancer.Tuberc. Respir. Dis.202386111310.4046/trd.2022.0066 36196556
    [Google Scholar]
  15. GreenwaltI. ZazaN. DasS. LiB.D. Precision medicine and targeted therapies in breast cancer.Surg. Oncol. Clin. N. Am.2020291516210.1016/j.soc.2019.08.004 31757313
    [Google Scholar]
  16. PetroniG. BuquéA. CoussensL.M. GalluzziL. Targeting oncogene and non-oncogene addiction to inflame the tumour microenvironment.Nat. Rev. Drug Discov.202221644046210.1038/s41573‑022‑00415‑5 35292771
    [Google Scholar]
  17. DongB. ZhuY.M. Molecular targeted therapy for cancer.Chin. J. Cancer201029334034510.5732/cjc.009.10313 20193122
    [Google Scholar]
  18. ZhaoJ. WuN. ZhangS.C. ZhaoZ.W. LiL.J. LiuJ.T. [New advances in targeted therapy for breast cancer].Chin. J. Oncol.2020425353361 32482023
    [Google Scholar]
  19. BolivarL.A. MoraP.E. VillegasV.E. LagosR.M. Resistance and overcoming resistance in breast cancer.Breast Cancer (Dove Med. Press)20201221122910.2147/BCTT.S270799 33204149
    [Google Scholar]
  20. PeuskensJ. The evolving definition of treatment resistance.J. Clin. Psychiatry199960Suppl. 1248 10372602
    [Google Scholar]
  21. RyanC.J. MehtaI. KebabciN. AdamsD.J. Targeting synthetic lethal paralogs in cancer.Trends Cancer20239539740910.1016/j.trecan.2023.02.002 36890003
    [Google Scholar]
  22. YangH. CuiW. WangL. Epigenetic synthetic lethality approaches in cancer therapy.Clin. Epigenetics201911113610.1186/s13148‑019‑0734‑x 31590683
    [Google Scholar]
  23. KaiserC.A. SchekmanR. Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway.Cell199061472373310.1016/0092‑8674(90)90483‑U 2188733
    [Google Scholar]
  24. BenderA. PringleJ.R. Use of a screen for synthetic lethal and multicopy suppressee mutants to identify two new genes involved in morphogenesis in Saccharomyces cerevisiae.Mol. Cell. Biol.199111312951305 1996092
    [Google Scholar]
  25. IglehartJ.D. SilverD.P. Synthetic lethality--a new direction in cancer-drug development.N. Engl. J. Med.2009361218919110.1056/NEJMe0903044 19553640
    [Google Scholar]
  26. NagelR. SemenovaE.A. BernsA. Drugging the addict: Non‐oncogene addiction as a target for cancer therapy.EMBO Rep.201617111516153110.15252/embr.201643030 27702988
    [Google Scholar]
  27. GallmeierE. KernS.E. Absence of specific cell killing of the BRCA2-deficient human cancer cell line CAPAN1 by poly(ADP-ribose) polymerase inhibition.Cancer Biol. Ther.20054770370610.4161/cbt.4.7.1909 16082177
    [Google Scholar]
  28. PiliéP.G. TangC. MillsG.B. YapT.A. State-of-the-art strategies for targeting the DNA damage response in cancer.Nat. Rev. Clin. Oncol.20191628110410.1038/s41571‑018‑0114‑z 30356138
    [Google Scholar]
  29. LiS. TopatanaW. JuengpanichS. CaoJ. HuJ. ZhangB. MaD. CaiX. ChenM. Development of synthetic lethality in cancer: Molecular and cellular classification.Signal Transduct. Target. Ther.20205124110.1038/s41392‑020‑00358‑6 33077733
    [Google Scholar]
  30. DingM.G. Ragod.J.P. TrumpowerB.L. Combining inhibitor resistance-conferring mutations in cytochrome b creates conditional synthetic lethality in saccharomyces cerevisiae.J. Biol. Chem.2009284138478848510.1074/jbc.M809278200 19179332
    [Google Scholar]
  31. BrunenD. BernardsR. Exploiting synthetic lethality to improve cancer therapy.Nat. Rev. Clin. Oncol.201714633133210.1038/nrclinonc.2017.46 28352131
    [Google Scholar]
  32. LiuQ.W. YangZ.W. TangQ.H. WangW.E. ChuD.S. JiJ.F. FanQ.Y. JiangH. YangQ.X. ZhangH. LiuX.Y. XuX.S. WangX.F. LiuJ.B. FuD. TaoK. YuH. The power and the promise of synthetic lethality for clinical application in cancer treatment.Biomed. Pharmacother.202417211628810.1016/j.biopha.2024.116288 38377739
    [Google Scholar]
  33. MudassarF. ShenH. CookK.M. HauE. Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment.J. Med. Imaging Radiat. Oncol.202266456057410.1111/1754‑9485.13416 35466515
    [Google Scholar]
  34. RyanC.J. DevakumarL.P.S. PettittS.J. LordC.J. Complex synthetic lethality in cancer.Nat. Genet.202355122039204810.1038/s41588‑023‑01557‑x 38036785
    [Google Scholar]
  35. FerrariE. LuccaC. FoianiM. A lethal combination for cancer cells: Synthetic lethality screenings for drug discovery.Eur. J. Cancer20104628892895
    [Google Scholar]
  36. TopatanaW. JuengpanichS. LiS. CaoJ. HuJ. LeeJ. SuliyantoK. MaD. ZhangB. ChenM. CaiX. Advances in synthetic lethality for cancer therapy: Cellular mechanism and clinical translation.J. Hematol. Oncol.202013111810.1186/s13045‑020‑00956‑5 32883316
    [Google Scholar]
  37. RyanC.J. BajramiI. LordC.J. Synthetic lethality and cancer – penetrance as the major barrier.Trends Cancer201841067168310.1016/j.trecan.2018.08.003 30292351
    [Google Scholar]
  38. KuA.A. HuH.M. ZhaoX. ShahK.N. KongaraS. WuD. McCormickF. BalmainA. BandyopadhyayS. Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility.Nat. Commun.2020111237510.1038/s41467‑020‑16078‑y 32398776
    [Google Scholar]
  39. MartinM.C. ZengG. YuJ. SchiltzG.E. Small molecule approaches for targeting the polycomb repressive complex 2 (PRC2) in cancer.J. Med. Chem.20206324153441537010.1021/acs.jmedchem.0c01344 33283516
    [Google Scholar]
  40. AliR. KawazA.A. TossM.S. GreenA.R. MiligyI.M. MesquitaK.A. SeedhouseC. MirzaS. BandV. RakhaE.A. MadhusudanS. Targeting PARP1 in XRCC1-deficient sporadic invasive breast cancer or preinvasive ductal carcinoma in situ induces synthetic lethality and chemoprevention.Cancer Res.201878246818682710.1158/0008‑5472.CAN‑18‑0633 30297533
    [Google Scholar]
  41. KinowakiY. TaguchiT. OnishiI. KirimuraS. KitagawaM. YamamotoK. Overview of ferroptosis and synthetic lethality strategies.Int. J. Mol. Sci.20212217927110.3390/ijms22179271 34502181
    [Google Scholar]
  42. FarrandL. ByunS. Induction of synthetic lethality by natural compounds targeting cancer signaling.Curr. Pharm. Des.2017232943114320 28699516
    [Google Scholar]
  43. McLornanD.P. ListA. MuftiG.J. Applying synthetic lethality for the selective targeting of cancer.N. Engl. J. Med.2014371181725173510.1056/NEJMra1407390 25354106
    [Google Scholar]
  44. ParrishP.C.R. ThomasJ.D. GabelA.M. KamlapurkarS. BradleyR.K. BergerA.H. Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome.Cell Rep.202136910959710.1016/j.celrep.2021.109597 34469736
    [Google Scholar]
  45. ChafeS.C. VizeacoumarF.S. VenkateswaranG. NemirovskyO. AwreyS. BrownW.S. McDonaldP.C. CartaF. MetcalfeA. KarasinskaJ.M. HuangL. MuthuswamyS.K. SchaefferD.F. RenoufD.J. SupuranC.T. VizeacoumarF.J. DedharS. Genome-wide synthetic lethal screen unveils novel CAIX-NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.Sci. Adv.2021735eabj036410.1126/sciadv.abj0364 34452919
    [Google Scholar]
  46. DeshpandeR. AsieduM.K. KlebigM. SutorS. KuzminE. NelsonJ. PiotrowskiJ. ShinH.S. YoshidaM. CostanzoM. BooneC. WigleD.A. MyersC.L. A comparative genomic approach for identifying synthetic lethal interactions in human cancer.Cancer Res.201373206128613610.1158/0008‑5472.CAN‑12‑3956 23980094
    [Google Scholar]
  47. AdamS. RossiS.E. MoattiN. ZompitM.D.M. XueY. NgT.F. QuilónA.A. DesjardinsJ. BhaskaranV. MartinoG. SetiaputraD. NoordermeerS.M. OhsumiT.K. HustedtN. SzilardR.K. ChaudharyN. MunroM. VelosoA. MeloH. YinS.Y. PappR. YoungJ.T.F. ZindaM. StuckiM. DurocherD. The CIP2A–TOPBP1 axis safeguards chromosome stability and is a synthetic lethal target for BRCA-mutated cancer.Nat. Cancer20212121357137110.1038/s43018‑021‑00266‑w 35121901
    [Google Scholar]
  48. LeeJ.S. NairN.U. DinstagG. ChapmanL. ChungY. WangK. SinhaS. ChaH. KimD. SchperbergA.V. SrinivasanA. LazarV. RubinE. HwangS. BergerR. BekerT. RonaiZ. HannenhalliS. GilbertM.R. KurzrockR. LeeS.H. AldapeK. RuppinE. Synthetic lethality-mediated precision oncology via the tumor transcriptome.Cell2021184924872502.e1310.1016/j.cell.2021.03.030 33857424
    [Google Scholar]
  49. SrivatsaS. MontazeriH. BiancoG. LlerenaC.M. MarinucciM. NgC.K.Y. PiscuoglioS. BeerenwinkelN. Discovery of synthetic lethal interactions from large-scale pan-cancer perturbation screens.Nat. Commun.2022131774810.1038/s41467‑022‑35378‑z 36517508
    [Google Scholar]
  50. LeeJ.S. DasA. ArnonJ.L. ArafehR. AuslanderN. DavidsonM. McGarryL. JamesD. AmzallagA. ParkS.G. ChengK. RobinsonW. AtiasD. StosselC. BuzhorE. SteinG. WaterfallJ.J. MeltzerP.S. GolanT. HannenhalliS. GottliebE. BenesC.H. SamuelsY. ShanksE. RuppinE. Harnessing synthetic lethality to predict the response to cancer treatment.Nat. Commun.201891254610.1038/s41467‑018‑04647‑1 29959327
    [Google Scholar]
  51. WangJ. ZhangQ. HanJ. ZhaoY. ZhaoC. YanB. DaiC. WuL. WenY. ZhangY. LengD. WangZ. YangX. HeS. BoX. Computational methods, databases and tools for synthetic lethality prediction.Brief. Bioinform.2022233bbac10610.1093/bib/bbac106 35352098
    [Google Scholar]
  52. GuoJ. LiuH. ZhengJ. SynLethDB: Synthetic lethality database toward discovery of selective and sensitive anticancer drug targets.Nucleic Acids Res.201644D1D1011D101710.1093/nar/gkv1108 26516187
    [Google Scholar]
  53. OughtredR. RustJ. ChangC. BreitkreutzB.J. StarkC. WillemsA. BoucherL. LeungG. KolasN. ZhangF. DolmaS. HuntingtonC.J. aryamontri, C.A.; Dolinski, K.; Tyers, M. The BIOGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions.Protein Sci.202130118720010.1002/pro.3978 33070389
    [Google Scholar]
  54. LiX. MishraS.K. WuM. ZhangF. ZhengJ. Syn-lethality: An integrative knowledge base of synthetic lethality towards discovery of selective anticancer therapies.BioMed Res. Int.201420141710.1155/2014/196034 24864230
    [Google Scholar]
  55. SchmidtE.E. PelzO. BuhlmannS. KerrG. HornT. BoutrosM. GenomeRNAi: A database for cell-based and in vivo RNAi phenotypes, 2013 update.Nucleic Acids Res.201341D1D1021D102610.1093/nar/gks1170 23193271
    [Google Scholar]
  56. ArnonJ.L. PfetzerN. WaldmanY.Y. McGarryL. JamesD. ShanksE. LudlowS.B. WeinstockA. GeigerT. ClemonsP.A. GottliebE. RuppinE. Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality.Cell201415851199120910.1016/j.cell.2014.07.027 25171417
    [Google Scholar]
  57. CostanzoM. VanderSluisB. KochE.N. BaryshnikovaA. PonsC. TanG. WangW. UsajM. HanchardJ. LeeS.D. PelechanoV. StylesE.B. BillmannM. Leeuwenv.J. Dykv.N. LinZ.Y. KuzminE. NelsonJ. PiotrowskiJ.S. SrikumarT. BahrS. ChenY. DeshpandeR. KuratC.F. LiS.C. LiZ. UsajM.M. OkadaH. PascoeN. LuisS.B.J. SharifpoorS. ShuteriqiE. SimpkinsS.W. SniderJ. SureshH.G. TanY. ZhuH. DogninM.N. JanjicV. PrzuljN. TroyanskayaO.G. StagljarI. XiaT. OhyaY. GingrasA.C. RaughtB. BoutrosM. SteinmetzL.M. MooreC.L. RosebrockA.P. CaudyA.A. MyersC.L. AndrewsB. BooneC. A global genetic interaction network maps a wiring diagram of cellular function.Science20163536306aaf142010.1126/science.aaf1420 27708008
    [Google Scholar]
  58. Haaftenv.G. VastenhouwN.L. NollenE.A.A. PlasterkR.H.A. TijstermanM. Gene interactions in the DNA damage-response pathway identified by genome-wide RNA-interference analysis of synthetic lethality.Proc. Natl. Acad. Sci. USA200410135129921299610.1073/pnas.0403131101 15326288
    [Google Scholar]
  59. HölzenL. MitschkeJ. SchönichenC. HessM.E. EhrenfeldS. BoerriesM. MiethingC. BrummerT. ReinheckelT. RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells.Theranostics20221294348437310.7150/thno.68299 35673573
    [Google Scholar]
  60. DhanjalJ.K. RadhakrishnanN. SundarD. Identifying synthetic lethal targets using CRISPR/Cas9 system.Methods2017131667310.1016/j.ymeth.2017.07.007 28710008
    [Google Scholar]
  61. LiuF. XinM. FengH. ZhangW. LiaoZ. ShengT. WenP. WuQ. LiangT. ShiJ. ZhouR. HeK. GuZ. LiH. Cryo-shocked tumor cells deliver CRISPR-Cas9 for lung cancer regression by synthetic lethality.Sci. Adv.20241013eadk826410.1126/sciadv.adk8264 38552011
    [Google Scholar]
  62. WangC. WangG. FengX. ShepherdP. ZhangJ. TangM. ChenZ. SrivastavaM. McLaughlinM.E. NavoneN.M. HartG.T. ChenJ. Genome-wide CRISPR screens reveal synthetic lethality of RNASEH2 deficiency and ATR inhibition.Oncogene201938142451246310.1038/s41388‑018‑0606‑4 30532030
    [Google Scholar]
  63. SchäfferA.A. ChungY. KammulaA.V. RuppinE. LeeJ.S. A systematic analysis of the landscape of synthetic lethality-driven precision oncology.Med.2024517389
    [Google Scholar]
  64. BenfattoS. SerçinÖ. DejureF.R. AbdollahiA. ZenkeF.T. MardinB.R. Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality.Mol. Cancer202120111110.1186/s12943‑021‑01405‑8 34454516
    [Google Scholar]
  65. ParksM.M. KuryloC.M. DassR.A. BojmarL. LydenD. VincentC.T. BlanchardS.C. Variant ribosomal RNA alleles are conserved and exhibit tissue-specific expression.Sci. Adv.201842eaao066510.1126/sciadv.aao0665 29503865
    [Google Scholar]
  66. YangH.D. NamS.W. Pathogenic diversity of RNA variants and RNA variation-associated factors in cancer development.Exp. Mol. Med.202052458259310.1038/s12276‑020‑0429‑6 32346127
    [Google Scholar]
  67. BlackJ.R. JonesT.P. RuizM.C. LitovchenkoM. PuttickC. McGranahanN. RNA allelic frequencies of somatic mutations encode substantial functional information in cancersbioRxiv20232023.200310.1101/2023.03.09.531725
    [Google Scholar]
  68. BurrellR.A. SwantonC. Tumour heterogeneity and the evolution of polyclonal drug resistance.Mol. Oncol.2014861095111110.1016/j.molonc.2014.06.005 25087573
    [Google Scholar]
  69. WuD. WangD.C. ChengY. QianM. ZhangM. ShenQ. WangX. Roles of tumor heterogeneity in the development of drug resistance: A call for precision therapy.Semin. Cancer Biol.201742131910.1016/j.semcancer.2016.11.006 27840278
    [Google Scholar]
  70. HugleM. BelzK. FuldaS. Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs.Cell Death Differ.201522121946195610.1038/cdd.2015.59 26024389
    [Google Scholar]
  71. SanjivK. HagenkortA. MontañoC.J.M. KoolmeisterT. ReaperP.M. MortusewiczO. JacquesS.A. KuiperR.V. SchultzN. ScobieM. CharltonP.A. PollardJ.R. BerglundU.W. AltunM. HelledayT. Cancer specific synthetic lethality between atr and chk1 kinase activities (vol 14, pg 298, 2016).Cell Rep.201617123407341610.1016/j.celrep.2016.12.031 28009306
    [Google Scholar]
  72. ClarkC.C. WeitzelJ.N. O’ConnorT.R. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models.Mol. Cancer Ther.20121191948195810.1158/1535‑7163.MCT‑11‑0597 22778154
    [Google Scholar]
  73. DaiB. YooS-Y. BartholomeuszG. GrahamR.A. MajidiM. YanS. MengJ. JiL. CoombesK. MinnaJ.D. FangB. RothJ.A. KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer.Cancer Res.2013731755325543
    [Google Scholar]
  74. ZhangY. IshidaC.T. IshidaW. LoS-F.L. ZhaoJ. ShuC. BianchettiE. KleinerG. QuinteroS.M.J. QuinziiC.M. WesthoffM-A. MasslerK.G. CanollP. SiegelinM.D. Combined hdac and bromodomain protein inhibition reprograms tumor cell metabolism and elicits synthetic lethality in glioblastoma.Clin. Cancer Res.2018241639413954
    [Google Scholar]
  75. ChengC.K. GustafsonW.C. CharronE. HousemanB.T. ZunderE. GogaA. GrayN.S. PollokB. OakesS.A. JamesC.D. ShokatK.M. WeissW.A. FanQ.W. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma.Proc. Natl. Acad. Sci. USA201210931127221272710.1073/pnas.1202492109 22802621
    [Google Scholar]
  76. Khodairya.F. CarrA.M. DNA repair mutants defining G2 checkpoint pathways in Schizosaccharomyces pombe.EMBO J.19921141343135010.1002/j.1460‑2075.1992.tb05179.x 1563350
    [Google Scholar]
  77. BoldoghI. RamanaC.V. ChenZ. BiswasT. HazraT.K. GröschS. GrombacherT. MitraS. KainaB. Regulation of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling.Cancer Res.1998581739503956 9731508
    [Google Scholar]
  78. MengE. HannaA. SamantR. ShevdeL. The impact of hedgehog signaling pathway on dna repair mechanisms in human cancer.Cancers2015731333134810.3390/cancers7030839 26197339
    [Google Scholar]
  79. BossD.S. BeijnenJ.H. SchellensJ.H.M. Inducing synthetic lethality using PARP inhibitors.Curr. Clin. Pharmacol.20105319219510.2174/157488410791498798 20406170
    [Google Scholar]
  80. LordC.J. AshworthA. PARP inhibitors: Synthetic lethality in the clinic.Science201735563301152115810.1126/science.aam7344 28302823
    [Google Scholar]
  81. DengS. VlatkovicT. LiM. ZhanT. VeldwijkM.R. HerskindC. Targeting the DNA damage response and dna repair pathways to enhance radiosensitivity in colorectal cancer.Cancers (Basel)20221419487410.3390/cancers14194874 36230796
    [Google Scholar]
  82. ManiC. ReddyP.H. PalleK. DNA repair fidelity in stem cell maintenance, health, and disease.Biochim. Biophys. Acta Mol. Basis Dis.20201866416544410.1016/j.bbadis.2019.03.017 30953688
    [Google Scholar]
  83. RobbeJ. MorettaJ. VicierC. SabatierR. NoguèsC. GonçalvesA. [PARP inhibitors in breast cancer: Current clinical development and perspectives].Bull. Cancer2020107101024104110.1016/j.bulcan.2020.07.011 33004179
    [Google Scholar]
  84. MalumbresM. BarbacidM. Cell cycle, CDKs and cancer: A changing paradigm.Nat. Rev. Cancer20099315316610.1038/nrc2602 19238148
    [Google Scholar]
  85. PetrocelliT. PoonR. DruckerD.J. SlingerlandJ.M. RosenC.F. UVB radiation induces p21Cip1/WAF1 and mediates G1 and S phase checkpoints.Oncogene199612713871396 8622854
    [Google Scholar]
  86. KaelinW.G.Jr The concept of synthetic lethality in the context of anticancer therapy.Nat. Rev. Cancer20055968969810.1038/nrc1691 16110319
    [Google Scholar]
  87. SizemoreS.T. MohammadR. SizemoreG.M. NowsheenS. YuH. OstrowskiM.C. ChakravartiA. XiaF. Synthetic lethality of PARP inhibition and ionizing radiation is p53-dependent.Mol. Cancer Res.20181671092110210.1158/1541‑7786.MCR‑18‑0106 29592899
    [Google Scholar]
  88. GerstlG.R. CohenM. ShiloA. SuhS.S. BakàcsA. CoppolaL. KarniR. Splicing factor hnRNP A2/B1 regulates tumor suppressor gene splicing and is an oncogenic driver in glioblastoma.Cancer Res.201171134464447210.1158/0008‑5472.CAN‑10‑4410 21586613
    [Google Scholar]
  89. GallantJ.N. SheehanJ.H. ShaverT.M. BaileyM. LipsonD. ChandramohanR. BrewerM.R. YorkS.J. KrisM.G. PietenpolJ.A. LadanyiM. MillerV.A. AliS.M. MeilerJ. LovlyC.M. EGFR kinase domain duplication (EGFR -KDD) is a novel oncogenic driver in lung cancer that is clinically responsive to afatinib.Cancer Discov.20155111155116310.1158/2159‑8290.CD‑15‑0654 26286086
    [Google Scholar]
  90. CookP.J. ThomasR. KannanR. Leond.E.S. DrilonA. RosenblumM.K. ScaltritiM. BenezraR. VenturaA. Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target (vol 8, 15987, 2017).Nat. Commun.20189
    [Google Scholar]
  91. LeeD.W. RamakrishnanD. ValentaJ. ParneyI.F. BaylessK.J. SitcheranR. The NF-κB relb protein is an oncogenic driver of mesenchymal glioma.PLoS One201382e5748910.1371/journal.pone.0057489
    [Google Scholar]
  92. WangY. KaiserC.E. FrettB. LiH. Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators.J. Med. Chem.201356135219523010.1021/jm3017706 23566315
    [Google Scholar]
  93. UpretyD. AdjeiA.A. KRAS: From undruggable to a druggable cancer target.Cancer Treat. Rev.20208910207010.1016/j.ctrv.2020.102070 32711246
    [Google Scholar]
  94. JineshG.G. SambandamV. VijayaraghavanS. BalajiK. MukherjeeS. Molecular genetics and cellular events of K-Ras-driven tumorigenesis.Oncogene201837783984610.1038/onc.2017.377 29059163
    [Google Scholar]
  95. WangJ. HuK. GuoJ. ChengF. LvJ. JiangW. LuW. LiuJ. PangX. LiuM. Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK.Nat. Commun.2016711136310.1038/ncomms11363 27193833
    [Google Scholar]
  96. HoellerbauerP. AroraS. FeldmanH. CarterL. GirardE.J. CorrinP. OlsonJ.M. PaddisonP. Gene-12. emerging principles of synthetic lethality in glioblastoma.Neuro-oncol.201719Suppl. 6vi9510.1093/neuonc/nox168.387
    [Google Scholar]
  97. NingJ.F. StanciuM. HumphreyM.R. GorhamJ. WakimotoH. NishiharaR. LeesJ. ZouL. MartuzaR.L. WakimotoH. RabkinS.D. Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma.Nat. Commun.2019101291010.1038/s41467‑019‑10993‑5 31266951
    [Google Scholar]
  98. LuoJ. SoliminiN.L. ElledgeS.J. Principles of cancer therapy: Oncogene and non-oncogene addiction.Cell2009136582383710.1016/j.cell.2009.02.024 19269363
    [Google Scholar]
  99. SoliminiN.L. LuoJ. ElledgeS.J. Non-oncogene addiction and the stress phenotype of cancer cells.Cell2007130698698810.1016/j.cell.2007.09.007 17889643
    [Google Scholar]
  100. DaiC. WhitesellL. RogersA.B. LindquistS. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis.Cell200713061005101810.1016/j.cell.2007.07.020 17889646
    [Google Scholar]
  101. LuoJ. EmanueleM.J. LiD. CreightonC.J. SchlabachM.R. WestbrookT.F. WongK.K. ElledgeS.J. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.Cell2009137583584810.1016/j.cell.2009.05.006 19490893
    [Google Scholar]
  102. SzczurekE. MisraN. VingronM. Synthetic sickness or lethality points at candidate combination therapy targets in glioblastoma.Int. J. Cancer201313392123213210.1002/ijc.28235 23629686
    [Google Scholar]
  103. JohannessenT.C. OliveH.M.M. ZhuH. DenisovaO. GrudicA. LatifM.A. SaedH. VarugheseJ.K. RøslandG.V. YangN. SundstrømT. NordalA. TronstadK.J. WangJ. JohansenL.M. SimonsenA. JanjiB. WestermarckJ. BjerkvigR. PrestegardenL. Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide.Int. J. Cancer201914471735174510.1002/ijc.31912 30289977
    [Google Scholar]
  104. HoellerbauerP. AroraS. KufeldM. CarterL. GirardE.J. FeldmanH. CorrinP. OlsonJ.M. PaddisonP.J. Abstract 413: Emerging principles in synthetic lethality in glioblastoma.Cancer Res.20187813_Supplement41310.1158/1538‑7445.AM2018‑413
    [Google Scholar]
  105. GatenbyR.A. GilliesR.J. Why do cancers have high aerobic glycolysis?Nat. Rev. Cancer200441189189910.1038/nrc1478 15516961
    [Google Scholar]
  106. SchulzeA. HarrisA.L. How cancer metabolism is tuned for proliferation and vulnerable to disruption.Nature2012491742436437310.1038/nature11706 23151579
    [Google Scholar]
  107. McGuirkS. DelageA.Y. PierreS.J. Metabolic fitness and plasticity in cancer progression.Trends Cancer202061496110.1016/j.trecan.2019.11.009 31952781
    [Google Scholar]
  108. KremerJ.C. PrudnerB.C. LangeS.E.S. BeanG.R. SchultzeM.B. BrashearsC.B. RadykM.D. RedlichN. TzengS.C. KamiK. SheltonL. LiA. MorganZ. BomalaskiJ.S. TsukamotoT. McConathyJ. MichelL.S. HeldJ.M. TineV.B.A. Arginine deprivation inhibits the warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ass1-deficient cancers.Cell Rep.2017184991100410.1016/j.celrep.2016.12.077 28122247
    [Google Scholar]
  109. MaiW.X. GosaL. DanielsV.W. TaL. TsangJ.E. HigginsB. GilmoreW.B. BayleyN.A. HaratiM.D. LeeJ.T. YongW.H. KornblumH.I. BensingerS.J. MischelP.S. RaoP.N. ClarkP.M. CloughesyT.F. LetaiA. NathansonD.A. Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma.Nat. Med.201723111342135110.1038/nm.4418 29035366
    [Google Scholar]
  110. ZhangY. IshidaC.T. ShuC. KleinerG. QuinteroS.M.J. BianchettiE. QuinziiC.M. WesthoffM.A. MasslerK.G. SiegelinM.D. Inhibition of Bcl-2/Bcl-xL and c-MET causes synthetic lethality in model systems of glioblastoma.Sci. Rep.201881737310.1038/s41598‑018‑25802‑0 29743557
    [Google Scholar]
  111. YooS. CernaD. LiH. FlahertyS. TakebeN. ColemanC. Coleman, NAPRT1 and p53 status in cancer and normal cells modulate induction of ros induced by gmx1777/1778: Implication for synthetic lethality in tumors defective in NAPRT1 and p53 Inter.J. Rad. Oncol. Biol. Phys.201078S656
    [Google Scholar]
  112. MasslerK.G. IshidaC.T. BianchettiE. ZhangY. ShuC. TsujiuchiT. BanuM.A. GarciaF. RothK.A. BruceJ.N. CanollP. SiegelinM.D. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL.Nat. Commun.201781106710.1038/s41467‑017‑00984‑9 29057925
    [Google Scholar]
  113. BremnesR.M. DønnemT. SaadA.S. ShibliA.K. AndersenS. SireraR. CampsC. MarinezI. BusundL.T. The role of tumor stroma in cancer progression and prognosis: Emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer.J. Thorac. Oncol.20116120921710.1097/JTO.0b013e3181f8a1bd 21107292
    [Google Scholar]
  114. HatakeyamaM. NozawaH. Hallmarks of Cancer: After the next generation.Cancer Sci.2022113885885
    [Google Scholar]
  115. ChanN. PiresI.M. BencokovaZ. CoackleyC. LuotoK.R. BhogalN. LakshmanM. GottipatiP. OliverF.J. HelledayT. HammondE.M. BristowR.G. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.Cancer Res.201070208045805410.1158/0008‑5472.CAN‑10‑2352 20924112
    [Google Scholar]
  116. NegriJ.M. McMillinD.W. DelmoreJ. MitsiadesN. HaydenP. KlippelS. HideshimaT. ChauhanD. MunshiN.C. BuserC.A. PollardJ. RichardsonP.G. AndersonK.C. MitsiadesC.S. In vitro anti‐myeloma activity of the Aurora kinase inhibitor VE‐465.Br. J. Haematol.2009147567267610.1111/j.1365‑2141.2009.07891.x 19751238
    [Google Scholar]
  117. McMillinD.W. DelmoreJ. WeisbergE. NegriJ.M. GeerC.D. KlippelS. MitsiadesN. SchlossmanR.L. MunshiN.C. KungA.L. GriffinJ.D. RichardsonP.G. AndersonK.C. MitsiadesC.S. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity (vol 16, pg 483, 2010).Nat. Med.202410.1038/s41591‑024‑02847‑5
    [Google Scholar]
  118. ZhangW. LiuL. SuH. LiuQ. ShenJ. DaiH. ZhengW. LuY. ZhangW. BeiY. ShenP. Chimeric antigen receptor macrophage therapy for breast tumours mediated by targeting the tumour extracellular matrix.Br. J. Cancer20191211083784510.1038/s41416‑019‑0578‑3 31570753
    [Google Scholar]
  119. FlorosK.V. JacobS. KurupiR. FairchildC.K. HuB. PuchalapalliM. KoblinskiE.J. DozmorovM.G. BoikosS.A. ScaltritiM. FaberA.C. Targeting transcription of MCL-1 sensitizes HER2-amplified breast cancers to HER2 inhibitors.Cell Death Dis.202112217910.1038/s41419‑021‑03457‑6 33589591
    [Google Scholar]
  120. SchopfF.H. BieblM.M. BuchnerJ. The HSP90 chaperone machinery.Nat. Rev. Mol. Cell Biol.201718634536010.1038/nrm.2017.20 28429788
    [Google Scholar]
  121. PlummerR. SwaislandH. LeunenK. Herpenv.C.M.L. JerusalemG. GrèveD.J. LolkemaM.P. SoetekouwP. SørensenM.M. NielsenD. SpicerJ. FieldingA. SoK. BannisterW. MolifeL.R. Olaparib tablet formulation: Effect of food on the pharmacokinetics after oral dosing in patients with advanced solid tumours.Cancer Chemother. Pharmacol.201576472372910.1007/s00280‑015‑2836‑2 26242220
    [Google Scholar]
  122. BianY. KitagawaR. BansalP.K. FujiiY. StepanovA. KitagawaK. Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors.Proc. Natl. Acad. Sci. USA201411141628163310.1073/pnas.1315588111 24425774
    [Google Scholar]
  123. LeeJ.M. PeerC.J. YuM. AmableL. GordonN. AnnunziataC.M. HoustonN. GoeyA.K.L. SissungT.M. ParkerB. MinasianL. ChiouV.L. MurphyR.F. WidemannB.C. FiggW.D. KohnE.C. Sequence specific pharmacokinetic and pharmacodynamic phase i/ib study of olaparib tablets and carboplatin in women’s cancer.Clin. Cancer Res.20172361397140610.1158/1078‑0432.CCR‑16‑1546 27663600
    [Google Scholar]
/content/journals/ctmc/10.2174/0115680266349547241231051447
Loading
/content/journals/ctmc/10.2174/0115680266349547241231051447
Loading

Data & Media loading...


  • Article Type:
    Review Article
Keyword(s): cancer therapy; drug resistance; oncology; Synthetic lethality; tumor biology
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test