Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells

Autoři: Andrey A. Parkhitko aff001;  Arashdeep Singh aff003;  Sharon Hsieh aff004;  Yanhui Hu aff001;  Richard Binari aff001;  Christopher J. Lord aff006;  Sridhar Hannenhalli aff003;  Colm J. Ryan aff007;  Norbert Perrimon aff001
Působiště autorů: Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff002;  Cancer Data Science Laboratory, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America aff003;  Department of Biology, Boston University, Boston, Massachusetts, United States of America aff004;  Howard Hughes Medical Institute, Boston, Massachusetts, United States of America aff005;  CRUK Gene Function Laboratory, The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom aff006;  Systems Biology Ireland, University College Dublin, Dublin, Ireland aff007;  School of Computer Science, University College Dublin, Dublin, Ireland aff008
Vyšlo v časopise: Cross-species identification of PIP5K1-, splicing- and ubiquitin-related pathways as potential targets for RB1-deficient cells. PLoS Genet 17(2): e1009354. doi:10.1371/journal.pgen.1009354
Kategorie: Research Article


The RB1 tumor suppressor is recurrently mutated in a variety of cancers including retinoblastomas, small cell lung cancers, triple-negative breast cancers, prostate cancers, and osteosarcomas. Finding new synthetic lethal (SL) interactions with RB1 could lead to new approaches to treating cancers with inactivated RB1. We identified 95 SL partners of RB1 based on a Drosophila screen for genetic modifiers of the eye phenotype caused by defects in the RB1 ortholog, Rbf1. We validated 38 mammalian orthologs of Rbf1 modifiers as RB1 SL partners in human cancer cell lines with defective RB1 alleles. We further show that for many of the RB1 SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of RB1 was associated with improved patient survival. We investigated higher order combinatorial gene interactions by creating a novel Drosophila cancer model with co-occurring Rbf1, Pten and Ras mutations, and found that targeting RB1 SL genes in this background suppressed the dramatic tumor growth and rescued fly survival whilst having minimal effects on wild-type cells. Finally, we found that drugs targeting the identified RB1 interacting genes/pathways, such as UNC3230, PYR-41, TAK-243, isoginkgetin, madrasin, and celastrol also elicit SL in human cancer cell lines. In summary, we identified several high confidence, evolutionarily conserved, novel targets for RB1-deficient cells that may be further adapted for the treatment of human cancer.

Klíčová slova:

Breast cancer – Prostate cancer – Drosophila melanogaster – Eyes – Gastrointestinal cancers – Genetic screens – Lung and intrathoracic tumors – RNA interference


1. Priestley P, Baber J, Lolkema MP, Steeghs N, de Bruijn E, Shale C, et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature. 2019;575(7781):210–6. Epub 2019/10/28. doi: 10.1038/s41586-019-1689-y 31645765; PubMed Central PMCID: PMC6872491.

2. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002;2(2):103–12. Epub 2002/09/03. doi: 10.1016/s1535-6108(02)00102-2 12204530.

3. Dyson NJ. RB1: a prototype tumor suppressor and an enigma. Genes & development. 2016;30(13):1492–502. Epub 2016/07/13. doi: 10.1101/gad.282145.116 27401552; PubMed Central PMCID: PMC4949322.

4. Gordon GM, Du W. Conserved RB functions in development and tumor suppression. Protein Cell. 2011;2(11):864–78. Epub 2011/12/20. doi: 10.1007/s13238-011-1117-z 22180086; PubMed Central PMCID: PMC3271014.

5. Velez-Cruz R, Johnson DG. The Retinoblastoma (RB) Tumor Suppressor: Pushing Back against Genome Instability on Multiple Fronts. Int J Mol Sci. 2017;18(8). Epub 2017/08/17. doi: 10.3390/ijms18081776 28812991; PubMed Central PMCID: PMC5578165.

6. Lee JS, Das A, Jerby-Arnon L, Arafeh R, Auslander N, Davidson M, et al. Harnessing synthetic lethality to predict the response to cancer treatment. Nature communications. 2018;9(1):2546. Epub 2018/07/01. doi: 10.1038/s41467-018-04647-1 29959327; PubMed Central PMCID: PMC6026173.

7. O’Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer. Nat Rev Genet 2017;18(10):613–23. Epub 2017/06/27. doi: 10.1038/nrg.2017.47 28649135.

8. Magen A, Das Sahu A, Lee JS, Sharmin M, Lugo A, Gutkind JS, et al. Beyond Synthetic Lethality: Charting the Landscape of Pairwise Gene Expression States Associated with Survival in Cancer. Cell reports. 2019;28(4):938–48 e6. Epub 2019/07/25. doi: 10.1016/j.celrep.2019.06.067 31340155.

9. Edgar KA, Belvin M, Parks AL, Whittaker K, Mahoney MB, Nicoll M, et al. Synthetic lethality of retinoblastoma mutant cells in the Drosophila eye by mutation of a novel peptidyl prolyl isomerase gene. Genetics. 2005;170(1):161–71. Epub 2005/03/04. doi: 10.1534/genetics.104.036343 15744054; PubMed Central PMCID: PMC1449713.

10. Gordon GM, Du W. Targeting Rb inactivation in cancers by synthetic lethality. Am J Cancer Res. 2011;1(6):773–86. Epub 2011/08/05. 21814623; PubMed Central PMCID: PMC3147291.

11. Li B, Gordon GM, Du CH, Xu J, Du W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer cell. 2010;17(5):469–80. Epub 2010/05/19. doi: 10.1016/j.ccr.2010.03.019 20478529; PubMed Central PMCID: PMC2873973.

12. Wang H, Bauzon F, Ji P, Xu X, Sun D, Locker J, et al. Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet. 2010;42(1):83–8. Epub 2009/12/08. doi: 10.1038/ng.498 19966802; PubMed Central PMCID: PMC2990528.

13. Brough R, Gulati A, Haider S, Kumar R, Campbell J, Knudsen E, et al. Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer. Oncogene. 2018;37(43):5701–18. Epub 2018/06/20. doi: 10.1038/s41388-018-0368-z 29915391; PubMed Central PMCID: PMC6202330.

14. Nittner D, Lambertz I, Clermont F, Mestdagh P, Kohler C, Nielsen SJ, et al. Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation. Nature cell biology. 2012;14(9):958–65. Epub 2012/08/07. doi: 10.1038/ncb2556 22864477.

15. Dehainault C, Garancher A, Castera L, Cassoux N, Aerts I, Doz F, et al. The survival gene MED4 explains low penetrance retinoblastoma in patients with large RB1 deletion. Hum Mol Genet. 2014;23(19):5243–50. Epub 2014/05/27. doi: 10.1093/hmg/ddu245 24858910.

16. Gong X, Du J, Parsons SH, Merzoug FF, Webster Y, Iversen PW, et al. Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene. Cancer Discov. 2019;9(2):248–63. Epub 2018/10/31. doi: 10.1158/2159-8290.CD-18-0469 30373917.

17. Oser MG, Fonseca R, Chakraborty AA, Brough R, Spektor A, Jennings RB, et al. Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival. Cancer Discov. 2019;9(2):230–47. Epub 2018/10/31. doi: 10.1158/2159-8290.CD-18-0389 30373918; PubMed Central PMCID: PMC6368871.

18. Zhao J, Zhang Z, Liao Y, Du W. Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to mitotic inhibitor induced cell death. Am J Cancer Res. 2014;4(1):42–52. Epub 2014/02/01. 24482737; PubMed Central PMCID: PMC3902231.

19. McDonald ER, de Weck A, Schlabach MR, Billy E, Mavrakis KJ, Hoffman GR, et al. Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening. Cell. 2017;170(3):577–92 e10. Epub 2017/07/29. doi: 10.1016/j.cell.2017.07.005 28753431.

20. Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49(12):1779–84. Epub 2017/10/31. doi: 10.1038/ng.3984 29083409; PubMed Central PMCID: PMC5709193.

21. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map. Cell. 2017;170(3):564–76 e16. Epub 2017/07/29. doi: 10.1016/j.cell.2017.06.010 28753430; PubMed Central PMCID: PMC5667678.

22. Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, et al. Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance. Cell. 2016;164(1–2):293–309. Epub 2016/01/16. doi: 10.1016/j.cell.2015.11.062 26771497; PubMed Central PMCID: PMC4724865.

23. Nicolay BN, Gameiro PA, Tschop K, Korenjak M, Heilmann AM, Asara JM, et al. Loss of RBF1 changes glutamine catabolism. Genes & development. 2013;27(2):182–96. Epub 2013/01/17. doi: 10.1101/gad.206227.112 23322302; PubMed Central PMCID: PMC3566311.

24. Freeman M. Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 1996;87(4):651–60. Epub 1996/11/15. doi: 10.1016/s0092-8674(00)81385-9 8929534.

25. Nicolay BN, Bayarmagnai B, Moon NS, Benevolenskaya EV, Frolov MV. Combined inactivation of pRB and hippo pathways induces dedifferentiation in the Drosophila retina. PLoS Genet. 2010;6(4):e1000918. Epub 2010/04/28. doi: 10.1371/journal.pgen.1000918 20421993; PubMed Central PMCID: PMC2858677.

26. Vidal M, Wells S, Ryan A, Cagan R. ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res 2005;65(9):3538–41. Epub 2005/05/04. doi: 10.1158/0008-5472.CAN-04-4561 15867345.

27. Bach EA, Vincent S, Zeidler MP, Perrimon N. A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway. Genetics. 2003;165(3):1149–66. Epub 2003/12/12. 14668372; PubMed Central PMCID: PMC1462825.

28. Khurana V, Lu Y, Steinhilb ML, Oldham S, Shulman JM, Feany MB. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr Biol 2006;16(3):230–41. Epub 2006/02/08. doi: 10.1016/j.cub.2005.12.042 16461276.

29. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. Epub 2011/03/08. doi: 10.1016/j.cell.2011.02.013 21376230.

30. Costanzo M, VanderSluis B, Koch EN, Baryshnikova A, Pons C, Tan G, et al. A global genetic interaction network maps a wiring diagram of cellular function. Science (New York, NY. 2016;353(6306). Epub 2016/10/07. doi: 10.1126/science.aaf1420 27708008; PubMed Central PMCID: PMC5661885.

31. Kelley R, Ideker T. Systematic interpretation of genetic interactions using protein networks. Nat Biotechnol. 2005;23(5):561–6. Epub 2005/05/07. doi: 10.1038/nbt1096 15877074; PubMed Central PMCID: PMC2814446.

32. Collins SR, Miller KM, Maas NL, Roguev A, Fillingham J, Chu CS, et al. Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature. 2007;446(7137):806–10. Epub 2007/02/23. doi: 10.1038/nature05649 17314980.

33. Kaplow IM, Singh R, Friedman A, Bakal C, Perrimon N, Berger B. RNAiCut: automated detection of significant genes from functional genomic screens. Nat Methods 2009;6(7):476–7. Epub 2009/07/01. doi: 10.1038/nmeth0709-476 19564846.

34. Hu Y, Vinayagam A, Nand A, Comjean A, Chung V, Hao T, et al. Molecular Interaction Search Tool (MIST): an integrated resource for mining gene and protein interaction data. Nucleic acids research. 2018;46(D1):D567–D74. Epub 2017/11/21. doi: 10.1093/nar/gkx1116 29155944; PubMed Central PMCID: PMC5753374.

35. Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X, et al. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell. 2017;171(6):1437–52 e17. Epub 2017/12/02. doi: 10.1016/j.cell.2017.10.049 29195078; PubMed Central PMCID: PMC5990023.

36. Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science (New York, NY. 2006;313(5795):1929–35. Epub 2006/09/30. doi: 10.1126/science.1132939 17008526.

37. Corsello SM, Nagari RT, Spangler RD, Rossen J, Kocak M, Bryan JG, et al. Discovering the anticancer potential of non-oncology drugs by systematic viability profiling. Nature Cancer. 2020;1:235–48. doi: 10.1038/s43018-019-0018-6 32613204

38. Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP, Schubert M, et al. A Landscape of Pharmacogenomic Interactions in Cancer. Cell. 2016;166(3):740–54. Epub 2016/07/12. doi: 10.1016/j.cell.2016.06.017 27397505; PubMed Central PMCID: PMC4967469.

39. Seashore-Ludlow B, Rees MG, Cheah JH, Cokol M, Price EV, Coletti ME, et al. Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset. Cancer Discov. 2015;5(11):1210–23. Epub 2015/10/21. doi: 10.1158/2159-8290.CD-15-0235 26482930; PubMed Central PMCID: PMC4631646.

40. Qaddoumi I, Billups CA, Tagen M, Stewart CF, Wu J, Helton K, et al. Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. Cancer. 2012;118(22):5663–70. Epub 2012/04/21. doi: 10.1002/cncr.27563 22516936; PubMed Central PMCID: PMC3413782.

41. Coussy F, El-Botty R, Chateau-Joubert S, Dahmani A, Montaudon E, Leboucher S, et al. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci Transl Med. 2020;12(531). Epub 2020/02/23. doi: 10.1126/scitranslmed.aax2625 32075943.

42. Xiao H, Goodrich DW. doi: 10.1038/sj.onc.1208958 16091739 retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes. Oncogene. 2005;24(55):8105–13. Epub 2005/08/11. PubMed Central PMCID: PMC2799250.

43. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018;173(2):321–37 e10. Epub 2018/04/07. doi: 10.1016/j.cell.2018.03.035 29625050; PubMed Central PMCID: PMC6070353.

44. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature 2019;575(7782):299–309. Epub 2019/11/15. doi: 10.1038/s41586-019-1730-1 31723286.

45. Kuzmin E, VanderSluis B, Wang W, Tan G, Deshpande R, Chen Y, et al. Systematic analysis of complex genetic interactions. Science (New York, NY. 2018;360(6386). Epub 2018/04/21. doi: 10.1126/science.aao1729 29674565; PubMed Central PMCID: PMC6215713.

46. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science (New York, NY. 2017;355(6330):1152–8. Epub 2017/03/18. doi: 10.1126/science.aam7344 28302823; PubMed Central PMCID: PMC6175050.

47. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401–4. Epub 2012/05/17. doi: 10.1158/2159-8290.CD-12-0095 22588877; PubMed Central PMCID: PMC3956037.

48. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science signaling. 2013;6(269):pl1. Epub 2013/04/04. doi: 10.1126/scisignal.2004088 23550210; PubMed Central PMCID: PMC4160307.

49. Haley B, Foys B, Levine M. Vectors and parameters that enhance the efficacy of RNAi-mediated gene disruption in transgenic Drosophila. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(25):11435–40. Epub 2010/06/11. doi: 10.1073/pnas.1006689107 20534445; PubMed Central PMCID: PMC2895090.

50. Lu X, Chou TB, Williams NG, Roberts T, Perrimon N. Control of cell fate determination by p21ras/Ras1, an essential component of torso signaling in Drosophila. Genes Dev 1993;7(4):621–32. Epub 1993/04/01. doi: 10.1101/gad.7.4.621 8458578.

51. Gisselbrecht S, Skeath JB, Doe CQ, Michelson AM. heartless encodes a fibroblast growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo. Genes Dev 1996;10(23):3003–17. Epub 1996/12/01. doi: 10.1101/gad.10.23.3003 8957001.

52. Markstein M, Dettorre S, Cho J, Neumuller RA, Craig-Muller S, Perrimon N. Systematic screen of chemotherapeutics in Drosophila stem cell tumors. Proceedings of the National Academy of Sciences of the United States of America. 2014;111(12):4530–5. Epub 2014/03/13. doi: 10.1073/pnas.1401160111 24616500; PubMed Central PMCID: PMC3970492.

53. Biteau B, Karpac J, Supoyo S, Degennaro M, Lehmann R, Jasper H. Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet. 2010;6(10):e1001159. Epub 2010/10/27. doi: 10.1371/journal.pgen.1001159 20976250; PubMed Central PMCID: PMC2954830.

54. Tan HL, Sood A, Rahimi HA, Wang W, Gupta N, Hicks J, et al. Rb loss is characteristic of prostatic small cell neuroendocrine carcinoma. Clin Cancer Res. 2014;20(4):890–903. Epub 2013/12/11. doi: 10.1158/1078-0432.CCR-13-1982 24323898; PubMed Central PMCID: PMC3931005.

55. Cook R, Zoumpoulidou G, Luczynski MT, Rieger S, Moquet J, Spanswick VJ, et al. Direct involvement of retinoblastoma family proteins in DNA repair by non-homologous end-joining. Cell reports. 2015;10(12):2006–18. Epub 2015/03/31. doi: 10.1016/j.celrep.2015.02.059 25818292; PubMed Central PMCID: PMC4386026.

56. Hellwinkel OJ, Muller J, Pollmann A, Kabisch H. Osteosarcoma cell lines display variable individual reactions on wildtype p53 and Rb tumour-suppressor transgenes. J Gene Med 2005;7(4):407–19. Epub 2004/11/13. doi: 10.1002/jgm.684 15538723.

57. Jones RA, Robinson TJ, Liu JC, Shrestha M, Voisin V, Ju Y, et al. RB1 deficiency in triple-negative breast cancer induces mitochondrial protein translation. The Journal of clinical investigation. 2016;126(10):3739–57. Epub 2016/08/30. doi: 10.1172/JCI81568 27571409; PubMed Central PMCID: PMC5096803.

58. Robinson TJ, Liu JC, Vizeacoumar F, Sun T, Maclean N, Egan SE, et al. RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs. PLoS One. 2013;8(11):e78641. Epub 2013/11/23. doi: 10.1371/journal.pone.0078641 24265703; PubMed Central PMCID: PMC3827056.

59. O’Brien K, Matlin AJ, Lowell AM, Moore MJ. The biflavonoid isoginkgetin is a general inhibitor of Pre-mRNA splicing. The Journal of biological chemistry. 2008;283(48):33147–54. Epub 2008/10/02. doi: 10.1074/jbc.M805556200 18826947; PubMed Central PMCID: PMC2586251.

60. Pawellek A, McElroy S, Samatov T, Mitchell L, Woodland A, Ryder U, et al. Identification of small molecule inhibitors of pre-mRNA splicing. The Journal of biological chemistry. 2014;289(50):34683–98. Epub 2014/10/05. doi: 10.1074/jbc.M114.590976 25281741; PubMed Central PMCID: PMC4263873.

61. Chan CH, Morrow JK, Li CF, Gao Y, Jin G, Moten A, et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell. 2013;154(3):556–68. Epub 2013/08/06. doi: 10.1016/j.cell.2013.06.048 23911321; PubMed Central PMCID: PMC3845452.

62. Wright BD, Loo L, Street SE, Ma A, Taylor-Blake B, Stashko MA, et al. The lipid kinase PIP5K1C regulates pain signaling and sensitization. Neuron. 2014;82(4):836–47. Epub 2014/05/24. doi: 10.1016/j.neuron.2014.04.006 24853942; PubMed Central PMCID: PMC4074510.

63. Yang Y, Kitagaki J, Dai RM, Tsai YC, Lorick KL, Ludwig RL, et al. Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics. Cancer research. 2007;67(19):9472–81. Epub 2007/10/03. doi: 10.1158/0008-5472.CAN-07-0568 17909057.

64. Hyer ML, Milhollen MA, Ciavarri J, Fleming P, Traore T, Sappal D, et al. A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment. Nat Med. 2018;24(2):186–93. Epub 2018/01/16. doi: 10.1038/nm.4474 29334375.

65. Cascao R, Fonseca JE, Moita LF. Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases. Front Med (Lausanne). 2017;4:69. Epub 2017/07/01. doi: 10.3389/fmed.2017.00069 28664158; PubMed Central PMCID: PMC5471334.

66. Dynlacht BD, Brook A, Dembski M, Yenush L, Dyson N. DNA-binding and trans-activation properties of Drosophila E2F and DP proteins. Proceedings of the National Academy of Sciences of the United States of America. 1994;91(14):6359–63. Epub 1994/07/05. doi: 10.1073/pnas.91.14.6359 8022787; PubMed Central PMCID: PMC44201.

67. Du W, Vidal M, Xie JE, Dyson N. RBF, a novel RB-related gene that regulates E2F activity and interacts with cyclin E in Drosophila. Genes Dev 1996;10(10):1206–18. Epub 1996/05/15. doi: 10.1101/gad.10.10.1206 8675008.

68. Stevaux O, Dimova D, Frolov MV, Taylor-Harding B, Morris E, Dyson N. Distinct mechanisms of E2F regulation by Drosophila RBF1 and RBF2. The EMBO journal. 2002;21(18):4927–37. Epub 2002/09/18. doi: 10.1093/emboj/cdf501 12234932; PubMed Central PMCID: PMC126297.

69. Sawado T, Yamaguchi M, Nishimoto Y, Ohno K, Sakaguchi K, Matsukage A. dE2F2, a novel E2F-family transcription factor in Drosophila melanogaster. Biochem Biophys Res Commun 1998;251(2):409–15. Epub 1998/10/30. doi: 10.1006/bbrc.1998.9407 9792788.

70. Ohtani K, Nevins JR. Functional properties of a Drosophila homolog of the E2F1 gene. Molecular and cellular biology. 1994;14(3):1603–12. Epub 1994/03/01. doi: 10.1128/mcb.14.3.1603 8114698; PubMed Central PMCID: PMC358519.

71. Yadav AK, Srikrishna S, Gupta SC. Cancer Drug Development Using Drosophila as an in vivo Tool: From Bedside to Bench and Back. Trends Pharmacol Sci 2016;37(9):789–806. Epub 2016/06/15. doi: 10.1016/ 27298020.

72. Gonzalez C. Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nature reviews 2013;13(3):172–83. Epub 2013/02/08. doi: 10.1038/nrc3461 23388617.

73. Villegas SN. One hundred years of Drosophila cancer research: no longer in solitude. Disease models & mechanisms. 2019;12(4). Epub 2019/04/07. doi: 10.1242/dmm.039032 30952627; PubMed Central PMCID: PMC6505481.

74. Bangi E, Ang C, Smibert P, Uzilov AV, Teague AG, Antipin Y, et al. A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Sci Adv. 2019;5(5):eaav6528. Epub 2019/05/28. doi: 10.1126/sciadv.aav6528 31131321; PubMed Central PMCID: PMC6531007.

75. Dar AC, Das TK, Shokat KM, Cagan RL. Chemical genetic discovery of targets and anti-targets for cancer polypharmacology. Nature. 2012;486(7401):80–4. Epub 2012/06/09. doi: 10.1038/nature11127 22678283; PubMed Central PMCID: PMC3703503.

76. De Kegel B, Ryan CJ. Paralog buffering contributes to the variable essentiality of genes in cancer cell lines. PLoS Genet. 2019;15(10):e1008466. Epub 2019/10/28. doi: 10.1371/journal.pgen.1008466 31652272; PubMed Central PMCID: PMC6834290.

77. Ewen-Campen B, Mohr SE, Hu Y, Perrimon N. Accessing the Phenotype Gap: Enabling Systematic Investigation of Paralog Functional Complexity with CRISPR. Dev Cell 2017;43(1):6–9. Epub 2017/10/11. doi: 10.1016/j.devcel.2017.09.020 29017030.

78. Ryan CJ, Bajrami I, Lord CJ. Synthetic Lethality and Cancer—Penetrance as the Major Barrier. Trends Cancer 2018;4(10):671–83. Epub 2018/10/08. doi: 10.1016/j.trecan.2018.08.003 30292351.

79. Gonatopoulos-Pournatzis T, Aregger M, Brown KR, Farhangmehr S, Braunschweig U, Ward HN, et al. Genetic interaction mapping and exon-resolution functional genomics with a hybrid Cas9-Cas12a platform. Nat Biotechnol. 2020;38(5):638–48. Epub 2020/04/07. doi: 10.1038/s41587-020-0437-z 32249828.

80. Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A. Role of the SCFSkp2 ubiquitin ligase in the degradation of p21Cip1 in S phase. J Biol Chem 2003;278(28):25752–7. Epub 2003/05/06. doi: 10.1074/jbc.M301774200 12730199.

81. Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1999;1(4):193–9. Epub 1999/11/13. doi: 10.1038/12013 10559916.

82. Zhao H, Bauzon F, Fu H, Lu Z, Cui J, Nakayama K, et al. Skp2 deletion unmasks a p27 safeguard that blocks tumorigenesis in the absence of pRb and p53 tumor suppressors. Cancer cell. 2013;24(5):645–59. Epub 2013/11/16. doi: 10.1016/j.ccr.2013.09.021 24229711; PubMed Central PMCID: PMC3880806.

83. Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, et al. Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature. 2017;547(7663):355–9. Epub 2017/07/06. doi: 10.1038/nature23000 28678782; PubMed Central PMCID: PMC5896562.

84. Chow LM, Endersby R, Zhu X, Rankin S, Qu C, Zhang J, et al. Cooperativity within and among Pten, p53, and Rb pathways induces high-grade astrocytoma in adult brain. Cancer cell. 2011;19(3):305–16. Epub 2011/03/15. doi: 10.1016/j.ccr.2011.01.039 21397855; PubMed Central PMCID: PMC3060664.

85. Filtz EA, Emery A, Lu H, Forster CL, Karasch C, Hallstrom TC. Rb1 and Pten Co-Deletion in Osteoblast Precursor Cells Causes Rapid Lipoma Formation in Mice. PLoS One. 2015;10(8):e0136729. Epub 2015/09/01. doi: 10.1371/journal.pone.0136729 26317218; PubMed Central PMCID: PMC4552947.

86. Xie C, Lu H, Nomura A, Hanse EA, Forster CL, Parker JB, et al. Co-deleting Pten with Rb in retinal progenitor cells in mice results in fully penetrant bilateral retinoblastomas. Molecular cancer. 2015;14:93. Epub 2015/04/25. doi: 10.1186/s12943-015-0360-y 25907958; PubMed Central PMCID: PMC4411757.

87. Hill R, Song Y, Cardiff RD, Van Dyke T. Heterogeneous tumor evolution initiated by loss of pRb function in a preclinical prostate cancer model. Cancer Res 2005;65(22):10243–54. Epub 2005/11/17. doi: 10.1158/0008-5472.CAN-05-1579 16288012.

88. Ku SY, Rosario S, Wang Y, Mu P, Seshadri M, Goodrich ZW, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science (New York, NY. 2017;355(6320):78–83. Epub 2017/01/07. doi: 10.1126/science.aah4199 28059767; PubMed Central PMCID: PMC5367887.

89. Koh J, Enders GH, Dynlacht BD, Harlow E. Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition. Nature 1995;375(6531):506–10. Epub 1995/06/08. doi: 10.1038/375506a0 7777061.

90. Monahan KB, Rozenberg GI, Krishnamurthy J, Johnson SM, Liu W, Bradford MK, et al. Somatic p16(INK4a) loss accelerates melanomagenesis. Oncogene. 2010;29(43):5809–17. Epub 2010/08/11. doi: 10.1038/onc.2010.314 20697345; PubMed Central PMCID: PMC3007178.

91. Sewastianik T, Jiang M, Sukhdeo K, Patel SS, Roberts K, Kang Y, et al. Constitutive Ras signaling and Ink4a/Arf inactivation cooperate during the development of B-ALL in mice. Blood Adv. 2017;1(25):2361–74. Epub 2018/01/04. doi: 10.1182/bloodadvances.2017012211 29296886; PubMed Central PMCID: PMC5729631 interests.

92. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes & development. 2001;15(24):3249–62. Epub 2001/12/26. doi: 10.1101/gad.947701 11751631; PubMed Central PMCID: PMC312852.

93. Hu Y, Sopko R, Foos M, Kelley C, Flockhart I, Ammeux N, et al. FlyPrimerBank: an online database for Drosophila melanogaster gene expression analysis and knockdown evaluation of RNAi reagents. G3 (Bethesda). 2013;3(9):1607–16. Epub 2013/07/31. doi: 10.1534/g3.113.007021 23893746; PubMed Central PMCID: PMC3755921.

94. Hu Y, Comjean A, Perkins LA, Perrimon N, Mohr SE. GLAD: an Online Database of Gene List Annotation for Drosophila. J Genomics. 2015;3:75–81. Epub 2015/07/15. doi: 10.7150/jgen.12863 26157507; PubMed Central PMCID: PMC4495321.

95. Franz M, Lopes CT, Huck G, Dong Y, Sumer O, Bader GD. Cytoscape.js: a graph theory library for visualisation and analysis. Bioinformatics. 2016;32(2):309–11. Epub 2015/09/30. doi: 10.1093/bioinformatics/btv557 26415722; PubMed Central PMCID: PMC4708103.

96. Hu Y, Flockhart I, Vinayagam A, Bergwitz C, Berger B, Perrimon N, et al. An integrative approach to ortholog prediction for disease-focused and other functional studies. BMC bioinformatics. 2011;12:357. Epub 2011/09/02. doi: 10.1186/1471-2105-12-357 21880147; PubMed Central PMCID: PMC3179972.

97. Vinayagam A, Hu Y, Kulkarni M, Roesel C, Sopko R, Mohr SE, et al. Protein complex-based analysis framework for high-throughput data sets. Science signaling. 2013;6(264):rs5. Epub 2013/02/28. doi: 10.1126/scisignal.2003629 23443684; PubMed Central PMCID: PMC3756668.

98. Lord CJ, Quinn N, Ryan CJ. Integrative analysis of large-scale loss-of-function screens identifies robust cancer-associated genetic interactions. eLife. 2020;9. Epub 2020/05/29. doi: 10.7554/eLife.58925 32463358; PubMed Central PMCID: PMC7289598.

99. Corsello SM, Nagari RT, Spangler RD, Rossen J, Kocak M, Bryan JG, et al. Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling. Nat Cancer. 2020;1(2):235–48. Epub 2020/07/03. doi: 10.1038/s43018-019-0018-6 32613204; PubMed Central PMCID: PMC7328899.

100. Ghandi M, Huang FW, Jane-Valbuena J, Kryukov GV, Lo CC, McDonald ER, 3rd, et al. Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019;569(7757):503–8. Epub 2019/05/10. doi: 10.1038/s41586-019-1186-3 31068700; PubMed Central PMCID: PMC6697103.

101. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society: Series B (Methodological). 1995;57 (1):289–300. doi: 10.1111/j.2517-6161.1995.tb02031.x

Článek vyšel v časopise

PLOS Genetics

2021 Číslo 2
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Důležitost adherence při depresivním onemocnění
nový kurz
Autoři: MUDr. Eliška Bartečková, Ph.D.

Koncepce osteologické péče pro gynekology a praktické lékaře
Autoři: MUDr. František Šenk

Sekvenční léčba schizofrenie
Autoři: MUDr. Jana Hořínková, Ph.D.

Hypertenze a hypercholesterolémie – synergický efekt léčby
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se