Synthetic lethal vulnerabilities of cancer

Annual Review of Pharmacology and Toxicology

Volumn 55, Issue , 2015, Pages 513-531

  De La Cruz, Ferran Fece ^a   Gapp, Bianca V ^a   Nijman, Sebastian M B ^a  

^a ERICH SCHMID INSTITUTE OF MATERIALS SCIENCE   (Austria)

Author keywords

Clinical translation; Drugs; Genetic screens; Synthetic lethality

Indexed keywords

DNA; MYC PROTEIN; RNA; ANTINEOPLASTIC AGENT; TUMOR MARKER;

APOPTOSIS; CANCER CELL; CANCER MORTALITY; CANCER PATIENT; CELL VIABILITY; DNA DAMAGE; FUTUROLOGY; GENE FUNCTION; GENE IDENTIFICATION; GENE INTERACTION; GENETIC ASSOCIATION; GENETIC SCREENING; HUMAN; HUMAN CELL; LETHALITY; MUTATION; NEOPLASM; NONHUMAN; PHARMACOGENETICS; PRIORITY JOURNAL; REVIEW; RNA INTERFERENCE; SYNTHETIC LETHALITY; TRANSLATIONAL RESEARCH; TUMOR GENE; ANIMAL; CELL DEATH; DRUG DESIGN; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORK; GENE THERAPY; GENETIC EPIGENESIS; GENETICS; METABOLISM; MOLECULARLY TARGETED THERAPY; NEOPLASMS; PATHOLOGY; PROCEDURES; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL DEATH; DRUG DESIGN; EPIGENESIS, GENETIC; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE REGULATORY NETWORKS; GENETIC THERAPY; HUMANS; MOLECULAR TARGETED THERAPY; NEOPLASMS; SIGNAL TRANSDUCTION; TRANSLATIONAL MEDICAL RESEARCH; TUMOR MARKERS, BIOLOGICAL;

EID: 84920849491     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-010814-124511     Document Type: Review

References (131)

1. Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646-74
2. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. 2013. Cancer genome landscapes. Science 339:1546-58
3. Levitzki A. 2013. Tyrosine kinase inhibitors: views of selectivity, sensitivity, and clinical performance. Annu. Rev. Pharmacol. Toxicol. 53:161-85
4. Tebbutt N, Pedersen MW, Johns TG. 2013. Targeting the ERBB family in cancer: couples therapy. Nat. Rev. Cancer 13:663-73
5. Weinstein IB. 2002. Addiction to oncogenes-the Achilles heal of cancer. Science 297:63-64
6. Smida M, Nijman SM. 2012. Functional drug-gene interactions in lung cancer. Expert Rev. Mol. Diagn. 12:291-302
7. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, et al. 2013. Mutational landscape and significance across 12 major cancer types. Nature 502:333-39
8. Garraway LA, Janne PA. 2012. Circumventing cancer drug resistance in the era of personalizedmedicine. Cancer Discov. 2:214-26
9. Hartwell LH, Szankasi P, Roberts CJ, Murray AW, Friend SH. 1997. Integrating genetic approaches into the discovery of anticancer drugs. Science 278:1064-68
10. Bridges CB. 1922. The origin of variations in sexual and sex-limited characters. Am. Nat. 56:51-63
11. Dobzhansky T. 1946. Genetics of natural populations. Xiii. Recombination and variability in populations of Drosophila pseudoobscura. Genetics 31:269-90
12. Lucchesi JC. 1968. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanogaster. Genetics 59:37-44
13. Kaelin WG Jr. 2005. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5:689-98
14. Kaelin WG Jr. 2009. Synthetic lethality: A framework for the development of wiser cancer therapeutics. Genome Med. 1:99
15. Nijman SM. 2011. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett. 585:1-6
16. Ashworth A, Lord CJ, Reis-Filho JS. 2011. Genetic interactions in cancer progression and treatment. Cell 145:30-38
17. Tischler J, Lehner B, Fraser AG. 2008. Evolutionary plasticity of genetic interaction networks. Nat. Genet. 40:390-91
18. Luo J, Solimini NL, Elledge SJ. 2009. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823-37
19. Dobbelstein M, Moll U. 2014. Targeting tumour-supportive cellular machineries in anticancer drug development. Nat. Rev. Drug Discov. 13:179-96
20. Whitesell L, Lindquist SL. 2005. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5:761-72
21. Mair B, Kubicek S, Nijman SM. 2014. Exploiting epigenetic vulnerabilities for cancer therapeutics. Trends Pharmacol. Sci. 35:136-45
22. Hartman JL IV, Garvik B, Hartwell L. 2001. Principles for the buffering of genetic variation. Science 291:1001-4
23. Giaever G, Chu AM, Ni L, Connelly C, Riles L, et al. 2002. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418:387-91
24. Winzeler EA, Shoemaker DD, Astromoff A, Liang H, Anderson K, et al. 1999. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285:901-6
25. Costanzo M, Baryshnikova A, Bellay J, Kim Y, Spear ED, et al. 2010. The genetic landscape of a cell. Science 327:425-31
26. Hillenmeyer ME, Fung E, Wildenhain J, Pierce SE, Hoon S, et al. 2008. The chemical genomic portrait of yeast: uncovering a phenotype for all genes. Science 320:362-65
27. Dixon SJ, Costanzo M, Baryshnikova A, Andrews B, Boone C. 2009. Systematic mapping of genetic interaction networks. Annu. Rev. Genet. 43:601-25
28. Laufer C, Fischer B, Billmann M, Huber W, Boutros M. 2013. Mapping genetic interactions in human cancer cells with RNAi and multiparametric phenotyping. Nat. Methods 10:427-31
29. Queitsch C, Sangster TA, Lindquist S. 2002. Hsp90 as a capacitor of phenotypic variation. Nature 417:618-24
30. Kirschner M, Gerhart J. 1998. Evolvability. Proc. Natl. Acad. Sci. USA 95:8420-27
31. Masel J, Siegal ML. 2009. Robustness: mechanisms and consequences. Trends Genet. 25:395-403
32. Lum PY, Armour CD, Stepaniants SB, Cavet G, Wolf MK, et al. 2004. Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell 116:121-37
33. Lehar J, Stockwell BR, Giaever G, Nislow C. 2008. Combination chemical genetics. Nat. Chem. Biol. 4:674-81
34. Giaever G, Flaherty P, Kumm J, Proctor M, Nislow C, et al. 2004. Chemogenomic profiling: identifying the functional interactions of small molecules in yeast. Proc. Natl. Acad. Sci. USA 101:793-98
35. Parsons AB, Brost RL, Ding H, Li Z, Zhang C, et al. 2004. Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways. Nat. Biotechnol. 22:62-69
36. Parsons AB, Lopez A, Givoni IE, Williams DE, Gray CA, et al. 2006. Exploring the mode-of-action of bioactive compounds by chemical-genetic profiling in yeast. Cell 126:611-25
37. Hoon S, Smith AM, Wallace IM, Suresh S, Miranda M, et al. 2008. An integrated platform of genomic assays reveals small-molecule bioactivities. Nat. Chem. Biol. 4:498-506
38. Jarosz DF, Taipale M, Lindquist S. 2010. Protein homeostasis and the phenotypic manifestation of genetic diversity: principles and mechanisms. Annu. Rev. Genet. 44:189-216
39. McLellan J, ONeil N, Tarailo S, Stoepel J, Bryan J, et al. 2009. Synthetic lethal genetic interactions that decrease somatic cell proliferation in Caenorhabditis elegans identify the alternative RFC CTF18 as a candidate cancer drug target. Mol. Biol. Cell 20:5306-13
40. Sajesh BV, Bailey M, Lichtensztejn Z, Hieter P, McManus KJ. 2013. Synthetic lethal targeting of superoxide dismutase 1 selectively kills RAD54B-deficient colorectal cancer cells. Genetics 195:757-67
41. van Pel DM, Barrett IJ, Shimizu Y, Sajesh BV, Guppy BJ, et al. 2013. An evolutionarily conserved synthetic lethal interaction network identifiesFEN1as a broad-spectrum target for anticancer therapeutic development. PLOS Genet. 9:e1003254
42. Roguev A, Bandyopadhyay S, Zofall M, Zhang K, Fischer T, et al. 2008. Conservation and rewiring of functional modules revealed by an epistasis map in fission yeast. Science 322:405-10
43. Dixon SJ, Fedyshyn Y, Koh JL, Prasad TS, Chahwan C, et al. 2008. Significant conservation of synthetic lethal genetic interaction networks between distantly related eukaryotes. Proc. Natl. Acad. Sci. USA 105:16653-58
44. Boone C, Bussey H, Andrews BJ. 2007. Exploring genetic interactions and networks with yeast. Nat. Rev. Genet. 8:437-49
45. 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
46. Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, et al. 2009. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462:108-12
47. Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, et al. 2009. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137:821-34
48. Babij C, Zhang Y, Kurzeja RJ, Munzli A, Shehabeldin A, et al. 2011. STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res. 71:5818-26
49. Kumar MS, Hancock DC, Molina-Arcas M, Steckel M, East P, et al. 2012. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149:642-55
50. 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
51. 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
52. Muellner MK, Uras IZ, Gapp BV, Kerzendorfer C, Smida M, et al. 2011. A chemical-genetic screen reveals a mechanism of resistance to PI3K inhibitors in cancer. Nat. Chem. Biol. 7:787-93
53. Torrance CJ, Agrawal V, Vogelstein B, Kinzler KW. 2001. Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nat. Biotechnol. 19:940-45
54. Mohr S, Bakal C, Perrimon N. 2010. Genomic screening with RNAi: results and challenges. Annu. Rev. Biochem. 79:37-64
55. Brummelkamp TR, Bernards R. 2003. New tools for functional mammalian cancer genetics. Nat. Rev. Cancer 3:781-89
56. Ngo VN, Davis RE, Lamy L, Yu X, Zhao H, et al. 2006. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441:106-10
57. Schlabach MR, Luo J, Solimini NL, Hu G, Xu Q, et al. 2008. Cancer proliferation gene discovery through functional genomics. Science 319:620-24
58. Silva JM, Marran K, Parker JS, Silva J, Golding M, et al. 2008. Profiling essential genes in human mammary cells by multiplex RNAi screening. Science 319:617-20
59. Schnorrer F, Schonbauer C, Langer CC, Dietzl G, Novatchkova M, et al. 2010. Systematic genetic analysis of muscle morphogenesis and function in Drosophila. Nature 464:287-91
60. Pospisilik JA, Schramek D, Schnidar H, Cronin SJF, Nehme NT, et al. 2010. Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate. Cell 140:148-60
61. Neumuller RA, Richter C, Fischer A, Novatchkova M, Neumuller KG, Knoblich JA. 2011. Genomewide analysis of self-renewal in Drosophila neural stem cells by transgenic RNAi. Cell Stem Cell 8:580-93
62. Zender L, Xue W, Zuber J, Semighini CP, Krasnitz A, et al. 2008. An oncogenomics-based in vivo RNAi screen identifies tumor suppressors in liver cancer. Cell 135:852-64
63. Bric A, Miething C, Bialucha CU, Scuoppo C, Zender L, et al. 2009. Functional identification of tumorsuppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell 16:324-35
64. Beronja S, Janki P, Heller E, Lien WH, Keyes BE, et al. 2013. RNAi screens inmice identify physiological regulators of oncogenic growth. Nature 501:185-90
65. Schramek D, Sendoel A, Segal JP, Beronja S, Heller E, et al. 2014. Direct in vivo RNAi screen unveils myosin IIa as a tumor suppressor of squamous cell carcinomas. Science 343:309-13
66. Shoemaker RH. 2006. The NCI60 human tumour cell line anticancer drug screen. Nat. Rev. Cancer 6:813-23
67. Basu A, Bodycombe NE, Cheah JH, Price EV, Liu K, et al. 2013. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules. Cell 154:1151-61
68. Haibe-Kains B, El-Hachem N, Birkbak NJ, Jin AC, Beck AH, et al. 2013. Inconsistency in large pharmacogenomic studies. Nature 504:389-93
69. Hopkins AL. 2008. Network pharmacology: the next paradigm in drug discovery. Nat. Chem. Biol. 4:682-90
70. Schenone M, Dancik V, Wagner BK, Clemons PA. 2013. Target identification and mechanism of action in chemical biology and drug discovery. Nat. Chem. Biol. 9:232-40
71. Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE, et al. 2013. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155:552-66
72. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. 2013. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548-51
73. 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. Proc. Natl. Acad. Sci. USA 109:2860-65
74. Zhu Z, Aref AR, Cohoon TJ, Barbie TU, Imamura Y, et al. 2014. Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov. 4:452-65
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
76. Liu G, Gandara DR, Lara PN Jr, Raghavan D, Doroshow JH, et al. 2004. A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin. Cancer Res. 10:924-28
77. Guha M. 2012. Cyclin-dependent kinase inhibitors move into Phase III. Nat. Rev. Drug Discov. 11:892-94
78. Vicent S, Chen R, Sayles LC, Lin C, Walker RG, et al. 2010. Wilms tumor 1 (WT1) regulates KRASdriven oncogenesis and senescence in mouse and human models. J. Clin. Investig. 120:3940-52
79. 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
80. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. 2003. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3:285-96
81. Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, et al. 2007. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447:864-68
82. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, et al. 2012. Ferroptosis: an irondependent form of nonapoptotic cell death. Cell 149:1060-72
83. Shaw AT, Winslow MM, Magendantz M, Ouyang C, Dowdle J, et al. 2011. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc. Natl. Acad. Sci. USA 108:8773-78
84. Dang CV. 2012. MYC on the path to cancer. Cell 149:22-35
85. 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
86. Zaman S, Wang R, Gandhi V. 2014. Targeting the apoptosis pathway in hematologic malignancies. Leuk. Lymphoma 55:1980-92
87. Maris JM. 2010. Recent advances in neuroblastoma. N. Engl. J. Med. 362:2202-11
88. Molenaar JJ, Ebus ME, Geerts D, Koster J, Lamers F, et al. 2009. Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells. Proc. Natl. Acad. Sci. USA 106:12968-73
89. Goga A, Yang D, Tward AD, Morgan DO, Bishop JM. 2007. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat. Med. 13:820-27
90. Horiuchi D, Kusdra L, Huskey NE, Chandriani S, Lenburg ME, et al. 2012. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J. Exp. Med. 209:679-96
91. Kang J, Sergio CM, Sutherland RL, Musgrove EA. 2014. Targeting cyclin-dependent kinase 1 (CDK1) but not CDK4/6 or CDK2 is selectively lethal to MYC-dependent human breast cancer cells. BMC Cancer 14:32
92. den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, et al. 2010. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood 116:1498-505
93. Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM. 2010. Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc. Natl. Acad. Sci. USA 107:13836-41
94. Brockmann M, Poon E, Berry T, Carstensen A, Deubzer HE, et al. 2013. Small molecule inhibitors of Aurora-A induce proteasomal degradation of N-myc in childhood neuroblastoma. Cancer Cell 24:75-89
95. 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
96. 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
97. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, et al. 2011. TargetingMYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl. Acad. Sci. USA 108:16669-74
98. 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
99. Ott CJ, Kopp N, Bird L, Paranal RM, Qi J, et al. 2012. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood 120:2843-52
100. Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, et al. 2013. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 3:308-23
101. Bandopadhayay P, Bergthold G, Nguyen B, Schubert S, Gholamin S, et al. 2014. BET bromodomain inhibition of MYC-amplified medulloblastoma. Clin. Cancer Res. 20:912-25
102. Jackson SP, Bartek J. 2009. TheDNA-damage response in human biology and disease. Nature 461:1071-78
103. 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
104. 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
105. Turner N, Tutt A, Ashworth A. 2004. Hallmarks of BRCAness in sporadic cancers. Nat. Rev. Cancer 4:814-19
106. 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
107. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, et al. 2012. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med. 366:1382-92
108. Mateo J, Ong M, Tan DSP, Gonzalez MA, de Bono JS. 2013. Appraising iniparib, the PARP inhibitor that never was-what must we learn? Nat. Rev. Clin. Oncol. 10:688-96
109. OShaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, et al. 2011. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N. Engl. J. Med. 364:205-14
110. Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, et al. 2009. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1:315-22
111. Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G, et al. 2010. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood 116:4578-87
112. Reaper PM, Griffiths MR, Long JM, Charrier JD, MacCormick S, et al. 2011. Selective killing of ATMor p53-deficient cancer cells through inhibition of ATR. Nat. Chem. Biol. 7:428-30
113. Nijman SM, Friend SH. 2013. Potential of the synthetic lethality principle. Science 342:809-11
114. Arrowsmith J, Miller P. 2013. Trial watch: phase II and phase III attrition rates 2011-2012. Nat. Rev. Drug Discov. 12:569
115. Carette JE, Guimaraes CP, Varadarajan M, Park AS, Wuethrich I, et al. 2009. Haploid genetic screens in human cells identify host factors used by pathogens. Science 326:1231-35
116. Carette JE, Guimaraes CP, Wuethrich I, Blomen VA, Varadarajan M, et al. 2011. Global gene disruption in human cells to assign genes to phenotypes by deep sequencing. Nat. Biotechnol. 29:542-46
117. Elling U, Taubenschmid J, Wirnsberger G, OMalley R, Demers SP, et al. 2011. Forward and reverse genetics through derivation of haploid mouse embryonic stem cells. Cell Stem Cell 9:563-74
118. Pettitt SJ, Rehman FL, Bajrami I, Brough R, Wallberg F, et al. 2013. A genetic screen using the PiggyBac transposon in haploid cells identifies Parp1 as a mediator of olaparib toxicity. PLOS ONE 8:e61520
119. Burckstummer T, Banning C, Hainzl P, Schobesberger R, Kerzendorfer C, et al. 2013. A reversible gene trap collection empowers haploid genetics in human cells. Nat. Methods 10:965-71
120. Cong L, Ran FA, Cox D, Lin S, Barretto R, et al. 2013. Multiplex genome engineering using CRISPR/Cas systems. Science 339:819-23
121. Mali P, Yang L, Esvelt KM, Aach J, Guell M, et al. 2013. RNA-guided human genome engineering via Cas9. Science 339:823-26
122. Wang T, Wei JJ, Sabatini DM, Lander ES. 2014. Genetic screens in human cells using the CRISPR-Cas9 system. Science 343:80-84
123. 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
124. Toyoshima M, Howie HL, Imakura M, Walsh RM, Annis JE, et al. 2012. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc. Natl. Acad. Sci. USA 109:9545-50
125. Pourdehnad M, Truitt ML, Siddiqi IN, Ducker GS, Shokat KM, Ruggero D. 2013. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl. Acad. Sci. USA 110:11988-93
126. Martin SA, McCabe N, Mullarkey M, Cummins R, Burgess DJ, et al. 2010. DNApolymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17:235-48
127. Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, et al. 2011. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19:664-78
128. Sullivan KD, Padilla-Just N, Henry RE, Porter CC, Kim J, et al. 2012. ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. Nat. Chem. Biol. 8:646-54
129. Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, et al. 2013. Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci. TranslationalMed. 5:189ra78
130. Chan DA, Sutphin PD, Nguyen P, Turcotte S, Lai EW, et al. 2011. TargetingGLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Translational Med. 3:94ra70
131. Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, et al. 2013. LKB1inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143-58