1932

Abstract

Treatment with targeted drugs has primarily focused on the genes and pathways that are mutated in cancer, which severely limits the repertoire of drug targets. Synthetic lethality exploits the notion that the presence of a mutation in a cancer gene is often associated with a new vulnerability that can be targeted therapeutically, thus greatly expanding the arsenal of potential drug targets. Here we discuss both the experimental and the computational biology tools that can be used to identify synthetic lethal interactions. We also discuss strategies for using synthetic lethality to discover new drug targets and in the rational design of more potent drug combinations. We review the progress made and future opportunities offered by synthetic lethal approaches to treating cancer more effectively.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-042016-073434
2017-03-06
2024-11-06
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/1/1/annurev-cancerbio-042016-073434.html?itemId=/content/journals/10.1146/annurev-cancerbio-042016-073434&mimeType=html&fmt=ahah

Literature Cited

  1. Adjei AA, Cohen RB, Franklin W, Morris C, Wilson D. et al. 2008. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J. Clin. Oncol. 26:2139–46 [Google Scholar]
  2. Bansal M, Yang J, Karan C, Menden MP, Costello JC. et al. 2014. A community computational challenge to predict the activity of pairs of compounds. Nat. Biotechnol. 32:1213–22 [Google Scholar]
  3. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA. et al. 2012. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483:603–7 [Google Scholar]
  4. Bernards R. 2012. A missing link in genotype-directed cancer therapy. Cell 151:465–68 [Google Scholar]
  5. Bernards R, Brummelkamp TR, Beijersbergen RL. 2006. shRNA libraries and their use in cancer genetics. Nat. Methods 3:701–6 [Google Scholar]
  6. Berns K, Bernards R. 2012. Understanding resistance to targeted cancer drugs through loss of function genetic screens. Drug Resist. Update 15:268–75 [Google Scholar]
  7. Bitler BG, Aird KM, Garipov A, Li H, Amatangelo M. et al. 2015. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21:231–38 [Google Scholar]
  8. Blomen VA, Majek P, Jae LT, Bigenzahn JW, Nieuwenhuis J. et al. 2015. Gene essentiality and synthetic lethality in haploid human cells. Science 350:1092–96 [Google Scholar]
  9. Bommi-Reddy A, Almeciga I, Sawyer J, Geisen C, Li W. et al. 2008. Kinase requirements in human cells: III. Altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. PNAS 105:16484–89 [Google Scholar]
  10. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D. et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–17 [Google Scholar]
  11. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P. et al. 2011. Improved survival with vemurafenib in melanoma with BRAFV600E mutation. N. Engl. J. Med. 364:2507–16 [Google Scholar]
  12. Corcoran RB, Cheng KA, Hata AN, Faber AC, Ebi H. et al. 2013. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models. Cancer Cell 23:121–28 [Google Scholar]
  13. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H. et al. 2004. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N. Engl. J. Med. 351:337–45 [Google Scholar]
  14. Dai Z, Sheridan JM, Gearing LJ, Moore DL, Su S. et al. 2014. edgeR: a versatile tool for the analysis of shRNA-seq and CRISPR-Cas9 genetic screens. F1000Research 3:95 [Google Scholar]
  15. Davies H, Bignell GR, Cox C, Stephens P, Edkins S. et al. 2002. Mutations of the BRAF gene in human cancer. Nature 417:949–54 [Google Scholar]
  16. De Raedt T, Beert E, Pasmant E, Luscan A, Brems H. et al. 2014. PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514:247–51 [Google Scholar]
  17. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J. et al. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904–17 [Google Scholar]
  18. DeVita VT, DeVita-Raeburn E. 2015. The Death of Cancer New York: Sarah Crichton [Google Scholar]
  19. Diaz AA, Qin H, Ramalho-Santos M, Song JS. 2015. HiTSelect: a comprehensive tool for high-complexity-pooled screen analysis. Nucleic Acids Res 43:e16 [Google Scholar]
  20. Downward J. 2015. RAS synthetic lethal screens revisited: still seeking the elusive prize. Clin. Cancer Res. 21:1802–9 [Google Scholar]
  21. Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML. et al. 2007. Global reconstruction of the human metabolic network based on genomic and bibliomic data. PNAS 104:1777–82 [Google Scholar]
  22. Emerling BM, Hurov JB, Poulogiannis G, Tsukazawa KS, Choo-Wing R. et al. 2013. Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors. Cell 155:844–57 [Google Scholar]
  23. Evers B, Jastrzebski K, Heijmans JP, Grernrum W, Beijersbergen RL, Bernards R. 2016. CRISPR knockout screening outperforms shRNA and CRISPRi in identifying essential genes. Nat. Biotechnol. 34:631–33 [Google Scholar]
  24. Facchetti G, Zampieri M, Altafini C. 2012. Predicting and characterizing selective multiple drug treatments for metabolic diseases and cancer. BMC Syst. Biol. 6:115 [Google Scholar]
  25. Farber S, Diamond LK. 1948. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 238:787–93 [Google Scholar]
  26. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA. et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21 [Google Scholar]
  27. Fedier A, Schlamminger M, Schwarz VA, Haller U, Howell SB, Fink D. 2003. Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites. Ann. Oncol. 14:938–45 [Google Scholar]
  28. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB. et al. 2010. Selective inhibition of BET bromodomains. Nature 468:1067–73 [Google Scholar]
  29. Flobak A, Baudot A, Remy E, Thommesen L, Thieffry D. et al. 2015. Discovery of drug synergies in gastric cancer cells predicted by logical modeling. PLOS Comput. Biol. 11:e1004426 [Google Scholar]
  30. Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T. 2011. Predicting selective drug targets in cancer through metabolic networks. Mol. Syst. Biol. 7:501 [Google Scholar]
  31. Fong PC, Boss DS, Yap TA, Tutt A, Wu P. et al. 2009. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361:123–34 [Google Scholar]
  32. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A. et al. 2012. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483:570–75 [Google Scholar]
  33. Geutjes EJ, Bajpe PK, Bernards R. 2012. Targeting the epigenome for treatment of cancer. Oncogene 31:3827–44 [Google Scholar]
  34. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. 2014. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32:40–51 [Google Scholar]
  35. Helming KC, Wang X, Roberts CW. 2014a. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 26:309–17 [Google Scholar]
  36. Helming KC, Wang X, Wilson BG, Vazquez F, Haswell JR. et al. 2014b. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20:251–54 [Google Scholar]
  37. Hoffman GR, Rahal R, Buxton F, Xiang K, McAllister G. et al. 2014. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. PNAS 111:3128–33 [Google Scholar]
  38. Hsu TYT, Simon LM, Neill NJ, Marcotte R, Sayad A. et al. 2015. The spliceosome is a therapeutic vulnerability in MYC-driven cancer. Nature 525:384–88 [Google Scholar]
  39. Huang L, Li F, Sheng J, Xia X, Ma J. et al. 2014. DrugComboRanker: drug combination discovery based on target network analysis. Bioinformatics 30:i228–36 [Google Scholar]
  40. Iorio F, Knijnenburg T, Vis D, Bignell G, Menden M. et al. 2016. A landscape of pharmacogenomic interactions in cancer. Cell 166:740–54 [Google Scholar]
  41. Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J. et al. 2013. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 14:38–47 [Google Scholar]
  42. Jerby-Arnon L, Pfetzer N, Waldman YY, McGarry L, James D. et al. 2014. Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality. Cell 158:1199–209 [Google Scholar]
  43. Johnson J, Thijssen B, McDermott U, Garnett M, Wessels LF, Bernards R. 2016. Targeting the RB-E2F pathway in breast cancer. Oncogene 35:4829–35 [Google Scholar]
  44. Jones S, Wang TL, Shih IM, Mao TL, Nakayama K. et al. 2010. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330:228–31 [Google Scholar]
  45. Kampmann M, Bassik MC, Weissman JS. 2014. Functional genomics platform for pooled screening and generation of mammalian genetic interaction maps. Nat. Protoc. 9:1825–47 [Google Scholar]
  46. Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR. et al. 2012. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335:348–53 [Google Scholar]
  47. Klinger B, Sieber A, Fritsche-Guenther R, Witzel F, Berry L. et al. 2013. Network quantification of EGFR signaling unveils potential for targeted combination therapy. Mol. Syst. Biol. 9:673 [Google Scholar]
  48. Knutson SK, Wigle TJ, Warholic NM, Sneeringer CJ, Allain CJ. et al. 2012. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8:890–96 [Google Scholar]
  49. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O. et al. 2005. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352:786–92 [Google Scholar]
  50. Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ. et al. 2015. Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 33:4032–38 [Google Scholar]
  51. Kwong LN, Costello JC, Liu H, Jiang S, Helms TL. et al. 2012. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat. Med. 18:1503–10 [Google Scholar]
  52. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H. et al. 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372:2509–20 [Google Scholar]
  53. Li B, Gordon GM, Du CH, Xu J, Du W. 2010. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17:469–80 [Google Scholar]
  54. Li W, Xu H, Xiao T, Cong L, Love MI. et al. 2014. MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol 15:554 [Google Scholar]
  55. Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L. et al. 2012. Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature 483:608–12 [Google Scholar]
  56. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E. et al. 2008. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359:378–90 [Google Scholar]
  57. Lord CJ, McDonald S, Swift S, Turner NC, Ashworth A. 2008. A high-throughput RNA interference screen for DNA repair determinants of PARP inhibitor sensitivity. DNA Repair 7:2010–19 [Google Scholar]
  58. Luo J, Emanuele MJ, Li D, Creighton CJ, Schlabach MR. et al. 2009. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137:835–48 [Google Scholar]
  59. Luo T, Masson K, Jaffe JD, Silkworth W, Ross NT. et al. 2012. STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability. PNAS 109:2860–65 [Google Scholar]
  60. Malumbres M, Barbacid M. 2003. RAS oncogenes: the first 30 years. Nat. Rev. Cancer 3:459–65 [Google Scholar]
  61. Martin SA, McCarthy A, Barber LJ, Burgess DJ, Parry S. et al. 2009. Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. EMBO Mol. Med. 1:323–37 [Google Scholar]
  62. McCabe N, Turner NC, Lord CJ, Kluzek K, Bialkowska A. et al. 2006. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66:8109–15 [Google Scholar]
  63. Megchelenbrink W, Katzir R, Lu X, Ruppin E, Notebaart RA. 2015. Synthetic dosage lethality in the human metabolic network is highly predictive of tumor growth and cancer patient survival. PNAS 112:12217–22 [Google Scholar]
  64. Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER. et al. 2012. Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas. Clin. Cancer Res. 18:2515–25 [Google Scholar]
  65. Morandell S, Reinhardt HC, Cannell IG, Kim JS, Ruf DM. et al. 2013. A reversible gene-targeting strategy identifies synthetic lethal interactions between MK2 and p53 in the DNA damage response in vivo. Cell Rep 5:868–77 [Google Scholar]
  66. Nghiem P, Park PK, Kim Y, Vaziri C, Schreiber SL. 2001. ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. PNAS 98:9092–97 [Google Scholar]
  67. Ogiwara H, Sasaki M, Mitachi T, Oike T, Higuchi S. et al. 2016. Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression. Cancer Discov 6:430–45 [Google Scholar]
  68. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. 2013. K-RasG12C inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548–51 [Google Scholar]
  69. Pagliarini R, Shao W, Sellers WR. 2015. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep 16:280–96 [Google Scholar]
  70. Patricelli MP, Janes MR, Li LS, Hansen R, Peters U. et al. 2016. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316–29 [Google Scholar]
  71. Pfister SX, Markkanen E, Jiang Y, Sarkar S, Woodcock M. et al. 2015. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28:557–68 [Google Scholar]
  72. Popovici V, Budinska E, Tejpar S, Weinrich S, Estrella H. et al. 2012. Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. J. Clin. Oncol. 30:1288–95 [Google Scholar]
  73. Prahallad A, Bernards R. 2015. Opportunities and challenges provided by crosstalk between signalling pathways in cancer. Oncogene 35:1073–79 [Google Scholar]
  74. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R. et al. 2012. Unresponsiveness of colon cancer to BRAFV600E inhibition through feedback activation of EGFR. Nature 483:100–3 [Google Scholar]
  75. Puyol M, Martin A, Dubus P, Mulero F, Pizcueta P. et al. 2010. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18:63–73 [Google Scholar]
  76. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS. et al. 2013. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–83 [Google Scholar]
  77. Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB. 2007. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11:175–89 [Google Scholar]
  78. Rottmann S, Wang Y, Nasoff M, Deveraux QL, Quon KC. 2005. A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3β/FBW7 loss of function. PNAS 102:15195–200 [Google Scholar]
  79. Rudalska R, Dauch D, Longerich T, McJunkin K, Wuestefeld T. et al. 2014. In vivo RNAi screening identifies a mechanism of sorafenib resistance in liver cancer. Nat. Med. 20:1138–46 [Google Scholar]
  80. Sajesh BV, Guppy BJ, McManus KJ. 2013. Synthetic genetic targeting of genome instability in cancer. Cancers 5:739–61 [Google Scholar]
  81. Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S. et al. 2004. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431:1112–17 [Google Scholar]
  82. Shalem O, Sanjana NE, Hartenian E, Shi X, Scott DA. et al. 2014. Genome-scale CRISPR-Cas9 knockout screening in human cells. Science 343:84–87 [Google Scholar]
  83. Sherr CJ, Beach D, Shapiro GI. 2016. Targeting CDK4 and CDK6: from discovery to therapy. Cancer Discov 6:353–67 [Google Scholar]
  84. Solimini NL, Luo J, Elledge SJ. 2007. Non-oncogene addiction and the stress phenotype of cancer cells. Cell 130:986–88 [Google Scholar]
  85. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ. et al. 2008. Modelling Myc inhibition as a cancer therapy. Nature 455:679–83 [Google Scholar]
  86. Steckel M, Molina-Arcas M, Weigelt B, Marani M, Warne PH. et al. 2012. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res 22:1227–45 [Google Scholar]
  87. Sun C, Hobor S, Bertotti A, Zecchin D, Huang S. et al. 2014. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 7:86–93 [Google Scholar]
  88. Sun T, Roepman P, Popovici V, Michaut M, Majewski I. et al. 2012. A robust genomic signature for detection of colorectal cancer patients with microsatellite instability phenotype and high mutation frequency. J. Pathol. 228:586–95 [Google Scholar]
  89. Tang J, Karhinen L, Xu T, Szwajda A, Yadav B. et al. 2013. Target inhibition networks: predicting selective combinations of druggable targets to block cancer survival pathways. PLOS Comput. Biol. 9:e1003226 [Google Scholar]
  90. Tian S, Simon I, Moreno V, Roepman P, Tabernero J. et al. 2012. A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction. Gut 62:540–49 [Google Scholar]
  91. Turner NC, Lord CJ, Iorns E, Brough R, Swift S. et al. 2008. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J 27:1368–77 [Google Scholar]
  92. Unni AM, Lockwood WW, Zejnullahu K, Lee-Lin SQ, Varmus H. 2015. Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma. eLife 4:e06907 [Google Scholar]
  93. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM. et al. 2014. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4:94–109 [Google Scholar]
  94. Van De Wetering M, Francies HE, Francis JM, Bounova G, Iorio F. et al. 2015. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161:933–45 [Google Scholar]
  95. van Geel RM, Elez E, Bendell JC, Faris JE, Lolkema MPJK. et al. 2014. Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer. J. Clin. Oncol. 32:3514 [Google Scholar]
  96. Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A. et al. 2016. A vulnerability of a subset of colon cancers with potential clinical utility. Cell 165:317–30 [Google Scholar]
  97. Venkitaraman AR. 2002. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–82 [Google Scholar]
  98. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A. et al. 2008. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359:1116–27 [Google Scholar]
  99. Vidigal JA, Ventura A. 2015. Rapid and efficient one-step generation of paired gRNA CRISPR-Cas9 libraries. Nat. Commun. 6:8083 [Google Scholar]
  100. Vollebergh MA, Lips EH, Nederlof PM, Wessels LF, Schmidt MK. et al. 2011. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann. Oncol. 22:1561–70 [Google Scholar]
  101. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA. et al. 2014. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 4:61–68 [Google Scholar]
  102. Wang H, Bauzon F, Ji P, Xu X, Sun D. et al. 2010. Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/ mice. Nat. Genet. 42:83–88 [Google Scholar]
  103. Wang L, Xiong H, Wu F, Zhang Y, Wang J. et al. 2014a. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep. 8:1461–74 [Google Scholar]
  104. Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O'Connor PM. 1996. UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J. Natl. Cancer Inst. 88:956–65 [Google Scholar]
  105. Wang T, Wei JJ, Sabatini DM, Lander ES. 2014b. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343:80–84 [Google Scholar]
  106. Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL, Quon KC. 2004. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5:501–12 [Google Scholar]
  107. Weinstein IB. 2002. Addiction to oncogenes—the Achilles heal of cancer. Science 297:63–64 [Google Scholar]
  108. Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA. et al. 2013. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45:1113–20 [Google Scholar]
  109. Wessels LF, Van Welsem T, Hart AA, Van't Veer LJ, Reinders MJ, Nederlof PM. 2002. Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 62:7110–17 [Google Scholar]
  110. Williams R. 2015. Discontinued in 2013: oncology drugs. Expert Opin. Investig. Drugs 24:95–110 [Google Scholar]
  111. Winter J, Breinig M, Heigwer F, Brugemann D, Leible S. et al. 2016. caRpools: an R package for exploratory data analysis and documentation of pooled CRISPR/Cas9 screens. Bioinformatics 32:632–34 [Google Scholar]
  112. Wong AS, Choi GC, Cui CH, Pregernig G, Milani P. et al. 2016. Multiplexed barcoded CRISPR-Cas9 screening enabled by CombiGEM. PNAS 113:2544–49 [Google Scholar]
  113. Zhao XM, Iskar M, Zeller G, Kuhn M, Van Noort V, Bork P. 2011. Prediction of drug combinations by integrating molecular and pharmacological data. PLOS Comput. Biol. 7:e1002323 [Google Scholar]
  114. Zhou Y, Zhu S, Cai C, Yuan P, Li C, Huang Y, Wei W. 2014. High-throughput screening of a CRISPR/Cas9 library for functional genomics in human cells. Nature 509:487–91 [Google Scholar]
  115. Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H. et al. 2011. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 478:524–28 [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-042016-073434
Loading
/content/journals/10.1146/annurev-cancerbio-042016-073434
Loading

Data & Media loading...

  • Article Type: Review Article
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