The concept of synthetic lethality in the context of anticancer therapy

Nature Reviews Cancer

Volumn 5, Issue 9, 2005, Pages 689-698

  Kaelin Jr , William G ^a  

^a HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 METHYLTHIOINOSINE; ALANOSINE; ANTIHYPERTENSIVE AGENT; ANTIINFECTIVE AGENT; ANTINEOPLASTIC AGENT; ANXIOLYTIC AGENT; BORTEZOMIB; CAFFEINE; CISPLATIN; CYTOTOXIC AGENT; DNA TOPOISOMERASE INHIBITOR; ETOPOSIDE; GYRASE INHIBITOR; HEAT SHOCK PROTEIN 90; HYPOCHOLESTEROLEMIC AGENT; IMATINIB; MAMMALIAN TARGET OF RAPAMYCIN; PROTEASOME INHIBITOR;

CANCER CELL; CANCER THERAPY; CHRONIC MYELOID LEUKEMIA; GENE FUNCTION; GENE MUTATION; HUMAN; LETHALITY; MULTIPLE MYELOMA; NONHUMAN; PRIORITY JOURNAL; REVIEW; SAFETY; SOMATIC CELL; TESTIS CANCER; ANIMAL; BIOLOGICAL MODEL; GENETICS; LETHAL GENE; NEOPLASM;

ANIMALS; ANTINEOPLASTIC AGENTS; GENES, LETHAL; HUMANS; MODELS, GENETIC; NEOPLASMS;

EID: 25444497278     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1691     Document Type: Review

References (110)

1. Kaelin, W. G. Jr. Choosing anticancer drug targets in the postgenomic era. J. Clin. Invest. 104, 1503-1506 (1999).
2. Reddy, A. & Kaelin, W. G. Jr. Using cancer genetics to guide the selection of anticancer drug targets. Curr. Opin. Pharmacol. 2, 366-373 (2002).
3. Kaelin, W. G. Jr. Gleevec: prototype or outlier? Sci. STKE 2004, PE12 (2004). References 1-3 provide counter-arguments to naysayers who suggest that genetically complex cancers will never be successfully treated with drugs.
4. Hartman, J. T., Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001-1004 (2001).
5. Guarente, L. Synthetic enhancement in gene interaction: a genetic tool come of age. Trends Genet. 9, 362-366 (1993).
6. Kamb, A. Mutation load, functional overlap, and synthetic lethality in the evolution and treatment of cancer. J. Theor. Biol. 223, 205-213 (2003). This paper and reference 58 are thoughtful essays on maladaptive genetic changes in cancer cells that might render them vunerable to pharmacological attack.
7. Friend, S. & Oliff, A. Emerging uses for genomic information in drug discovery. N. Engl. J. Med. 338, 125-126 (1998).
8. Dobzhansky, T. Genetics of natural populations. XIII. Recombination and variability in populations of Drosophila pseudoobscura. Genetics 31, 269-290 (1946).
9. Lucchesi, J. C. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanogaster. Genetics 59, 37-44 (1968).
10. Sharom, J. R., Bellows, D. S. &Tyers, M. From large networks to small molecules. Curr. Opin. Chem. Biol. 8, 81-90 (2004). Excellent introduction to systems biology as applied to cancer and cancer pharmacology.
11. Kroll, E. S., Hyland, K. M., Hieter, P. & Li, J. J. Establishing genetic interactions by a synthetic dosage lethality phenotype. Genetics 143, 95-102 (1996).
12. Measday, V. & Hieter, P. Synthetic dosage lethality. Methods Enzymol. 350, 316-326 (2002).
13. Li, J. J. & Herskowitz, I. Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. Science 262, 1870-1874 (1993).
14. Tong, A. H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364-2368 (2001).
15. Tong, A. H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808-813 (2004). References 14 and 15 provide a glimpse into the complexity of synthetic lethal networks in yeast.
16. Hartwell, L., Szankasi, P., Roberts, C., Murray, A. & Friend, S. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064-1068 (1997). This seminal paper argues that synthetic lethal interactions be exploited to arrive at safer, more efficacious cancer drugs.
17. Sellers, W. R. & Kaelin, W. G. Jr. Role of the retinoblastoma protein in the pathogenesis of human cancer. J. Clin. Oncol. 15, 3301-3312 (1997).
18. Nip, J. et al. E2F-1 cooperates with topoisomerase II inhibition and DNA damage to selectively augment p53-independent apoptosis. Mol. Cell. Biol. 17, 1049-1056 (1997).
19. Almasan, A. et al. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Proc. Natl Acad. Sci. USA 92, 5436-5440 (1995).
20. Banerjee, D. et al. Role of E2F-1 in chemosensitivity. Cancer Res. 58, 4292-4296 (1998).
21. Dolma, S., Lessnick, S. L., Hahn, W. C. & Stockwell, B. R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3, 285-296 (2003).
22. Evan, G. I. & Vousden, K. H. Proliferation, cell cycle and apoptosis in cancer. Nature 411, 342-348 (2001).
23. Zaika, A., Irwin, M., Sansome, C. & Moll, U. M. Oncogenes induce and activate endogenous p73 protein. J. Biol. Chem. 276, 11310-11316 (2001).
24. Meng, R., Phillips, P. & El-Deiry, W. p53-independent increase in E2F-1 expression enhances the cytoxic effects of etoposide and of adriamycin. Intl J. Oncol. 14, 5-14 (1999).
25. Irwin, M. S. et al. Chemosensitivity linked to p73 function. Cancer Cell 3, 403-410 (2003).
26. Rutherford, S. L. & Lindquist, S. HSP90 as a capacitor for morphological evolution. Nature 396, 336-342 (1998).
27. Isaacs, J. S., Xu, W. & Neckers, L. Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 3, 213-217 (2003).
28. Workman, P. Altered states: selectively drugging the HSP90 cancer chaperone. Trends Mol. Med. 10, 47-51 (2004).
29. Neckers, L. & Neckers, K. Heat-shock protein 90 inhibitors as novel cancer chemotherapeutics - an update. Expert Opin. Emerg. Drugs 10, 137-149 (2005).
30. Goldberg, A. L. Protein degradation and protection against misfolded or damaged proteins. Nature 426, 895-899 (2003).
31. Rajkumar, S. V., Richardson, P. G., Hideshima, T. & Anderson, K. C. Proteasome inhibition as a novel therapeutic target in human cancer. J. Clin. Oncol. 23, 630-639 (2005).
32. Krek, W., Xu, G., & Livingston, D. M. Cydin A-kinase regulation of E2F1 DNA binding function underlies suppression of an S phase checkpoint. Cell 83, 1149-1158 (1995).
33. Dynlacht, B. D., Flores, O., Lees, J. A. & Harlow, E. Differential regulation of E2F transactivation by cyclin/CDK complexes. Genes Dev. 8, 1772-1786 (1994).
34. Krek, W. et al. Negative regulation of the growth-promoting transcription factor E2F-1 by a stably bound cyclin A-dependent protein kinase. Cell 78, 1-20 (1994).
35. Xu, M., Sheppard, K. A., Peng, C-Y., Yee, A. S. & Piwnica-Worms, H. Cyclin A/CDK2 binds directly to E2F1 and inhibits the DNA-binding activity of E2F1/DP1 by phosphorylation. Mol. Cell. Biol. 14, 8420-8431 (1994).
36. Parr, M. J. et al. Tumor-selective transgene expression in vivo mediated by an E2F-responsive adenoviral vector. Nature Med. 3, 1145-1149 (1997).
37. Chen, Y. et al. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc. Natl Acad. Sci. USA 96, 4325-4329 (1999).
38. Chen, W., Lee, J., Cho, S. Y. & Fine, H. A. Proteasome-mediated destruction of the cyclin A/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo. Cancer Res. 64, 3949-3957 (2004).
39. Mendoza, N. et al. Selective cyclin-dependent kinase 2/cyclin A antagonists that differ from ATP site inhibitors block tumor growth. Cancer Res. 63, 1020-1024 (2003).
40. Tetsu, O. & McCormick, F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3, 233-245 (2003).
41. Berthet, C., Aleem, E., Coppola, V., Tessarollo, L. & Kaldis, P. CDK2 knockout mice are viable. Curr. Biol. 13, 1775-1785 (2003).
42. Ortega, S. et al. Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nature Genet. 35, 25-31 (2003).
43. Schlegel, R. & Pardee, A. B. Caffeine-induced uncoupling of mitosis from the completion of DNA replication in mammalian cells. Science 232, 1264-1266 (1986).
44. Nishimoto, T., Ishida, R., Ajiro, K., Yamamoto, S. & Takahashi, T. The synthesis of protein(s) for chromosome condensation may be regulated by a post-transcriptional mechanism. J. Cell. Physiol. 109, 299-308 (1981).
45. Hall-Jackson, C. A., Cross, D. A., Morrice, N. & Smythe, C. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene 18, 6707-6713 (1999).
46. Sarkaria, J. N. et al. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res. 59, 4375-4382 (1999).
47. Nghiem, P., Park, P., Kim, Y., Vaziri, C. & Schreiber, S. ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proc. Natl Acad. Sci. USA 98, 9092-9097 (2001).
48. Sordella, R., Bell, D. W., Haber, D. A. & Settleman, J. Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305, 1163-1167 (2004).
49. Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129-2139 (2004).
50. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497-1500 (2004).
51. Pao, W. et al. EGF receptor gene mutations are common in lung cancers from 'never smokers' and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl Acad. Sci. USA 101, 13306-13311 (2004).
52. Weinstein, I. B. et al. Disorders in cell circuitry associated with multistage carcinogenesis: exploitable targets for cancer prevention and therapy. Clin. Cancer Res. 3, 2696-2702 (1997).
53. Weinstein, I. B. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Carcinogenesis 21, 857-864 (2000).
54. Weinstein, I. B. Cancer. Addiction to oncogenes - the Achilles heal of cancer. Science 297, 63-64 (2002). References 52-54, introduced the term 'oncogene addiction'.
55. Adams, P. & Kaelin, W. J. Jr. The cellular effects of E2F overexpression. Curr. Top. Microbiol. Immunol. 208, 79-93 (1996).
56. Sherr, C. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 60, 3689-3695 (2000).
57. Mills, G., Lu, Y. & Kohn, E. Linking molecular therapeutics to molecular diagnostics: inhibition of the FRAP/RAFT/TOR component of the PI3K pathway preferentially blocks PTEN mutant cells in vitro and in vivo. Proc. Natl Acad. Sci. USA 98, 10031-10033 (2001).
58. Kamb, A. Consequences of nonadaptive alterations in cancer. Mol. Biol. Cell 14, 2201-2205 (2003).
59. Neshat, M. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314-10319 (2001).
60. Frei, E. D. Gene deletion: a new target for cancer chemotherapy. Lancet 342, 662-664 (1993).
61. Cairns, P. et al. Frequency of homozygous deletion at p16/CDKN2 in primary human tumours. Nature Genet. 11, 210-212 (1995).
62. Li, W. et al. Status of methylthioadenosine phosphorylase and its impact on cellular response to L-alanosine and methylmercaptopurine riboside in human soft tissue sarcoma cells. Oncol. Res. 14, 373-379 (2004).
63. Wong, S. L. et al. Combining biological networks to predict genetic interactions. Proc. Natl Acad. Sci. USA 101, 15682-15687 (2004).
64. Simon, J. A. et al. Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae. Cancer Res. 60, 328-333 (2000).
65. Stockwell, B., Haggarty, S. & Schreiber, S. High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications. Chem. Biol. 6, 71-83 (1999). References 64 and 65 are two early examples of using isogenic cell lines to isolate compounds that kill cells in a genotype-specific manner.
66. Torrance, C., Agrawal, V., Vogelstein, B. & Kinzler, K. Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nature Biotechnol. 19, 940-945 (2001).
67. Bender, A. & Pringle, J. 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. 11, 1295-1305 (1991).
68. Simons, A., Dafni, N., Dotan, I., Oron, Y. & Canaani, D. Establishment of a chemical synthetic lethality screen in cultured human cells. Genome Res. 11, 266-273 (2001).
69. Simons, A., Dafni, N., Dotan, I., Oron, Y. & Canaani, D. Genetic synthetic lethality screen at the single gene level in cultured human cells. Nucleic Acids Res. 29, E100 (2001).
70. Fantin, V. R. & Leder, P. F16, a mitochondriotoxic compound, triggers apoptosis or necrosis depending on the genetic background of the target carcinoma cell. Cancer Res. 64, 329-336 (2004).
71. Fantin, V. R., Berardi, M. J., Scorrano, L., Korsmeyer, S. J. & Leder, P. A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth. Cancer Cell 2, 29-42 (2002).
72. Wang, Y. et al. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5, 501-512 (2004).
73. Haggarty, S. J., Clemons, P. A. & Schreiber, S. L. Chemical genomic profiling of biological networks using graph theory and combinations of small molecule perturbations. J. Am. Chem. Soc. 125, 10543-10545 (2003).
74. Borisy, A. A. et al. Systematic discovery of multicomponent therapeutics. Proc. Natl Acad. Sci. USA 100, 7977-7982 (2003).
75. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3-26 (2001).
76. Lipinski, C. A. Drug-like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Methods 44, 235-249 (2000).
77. Knockaert, M. et al. Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors. Chem. Biol. 7, 411-422 (2000).
78. Hultsch, T., Albers, M. W., Schreiber, S. L. & Hohman, R. J. Immunophilin ligands demonstrate common features of signal transduction leading to exocytosis or transcription. Proc. Natl Acad. Sci. USA 88, 6229-6233 (1991).
79. Baetz, K. et al. Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action. Proc. Natl Acad. Sci. USA 101, 4525-4230 (2004).
80. Giaever, G. et al. Genomic profiling of drug sensitivities via induced haploinsufficiency. Nature Genet. 21, 278-283 (1999).
81. Marton, M. et al. Drug target validation and identification of secondary drug target effects using DNA microarrays. Nature Med. 4, 1293-1301 (1998).
82. Lu, X. & Horvitz, H. R. lin-35 and lin-53, two genes that antagonize a C. elegans Ras pathway, encode proteins similar to RB and its binding protein RBAp48. Cell 95, 981-991 (1998).
83. Fay, D. S., Large, E., Han, M. & Darland, M. lin-35/Rb and ubc-78, an E2 ubiquitin-conjugating enzyme, function redundantly to control pharyngeal morphogenesis in C. elegans. Development 130, 3319-3330 (2003).
84. Fay, D. S., Keenan, S. & Han, M. fzr-1 and lin-35/Rb function redundantly to control cell proliferation in C. elegans as revealed by a nonbiased synthetic screen. Genes Dev. 16, 503-517 (2002).
85. Edgar, K. A. et al. Synthetic lethality of retinoblastoma mutant cells in the Drosophila eye by mutation of a novel peptidyl prolyl isomerase gene. Genetics 170, 161-171 (2005).
86. Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231-237 (2003).
87. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268-272 (2003).
88. Cherry, S. et al. Genome-wide RNAi screen reveals a specific sensitivity of IRES-containing RNA viruses to host translation inhibition. Genes Dev. 19, 445-452 (2005).
89. Rual, J. F. et al. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162-2168 (2004).
90. Willingham, A. T., Deveraux, Q. L., Hampton, G. M. & Aza-Blanc, P. RNAi and HTS: exploring cancer by systematic loss-of-function. Oncogene 23, 8392-8400 (2004).
91. Elbashir, S. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494-498 (2001).
92. Brummelkamp, T. R., Bernards, R. & Agami, R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2, 243-247 (2002).
93. Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550-553 (2002).
94. Lee, N. S. et al. Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nature Biotechnol. 20, 500-505 (2002).
95. Paddison, P. J., Caudy, A. A., Bernstein, E., Hannon, G. J. & Conklin, D. S. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 16, 948-958 (2002).
96. Sui, G. et al. A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc. Natl Acad. Sci. USA 99, 5515-5520 (2002).
97. Berns, K. et al. A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature 428, 431-437 (2004).
98. Paddison, P. J. et al. A resource for large-scale RNA-interference-based screens in mammals. Nature 428, 427-431 (2004). References 97 and 98 suggest that it should eventually be possible to carry out synthetic lethal screens in isogenic human cell-line pairs using barcoded shRNA libraries.
99. Shirane, D. et al. Enzymatic production of RNAi libraries from cDNAs. Nature Genet. 36, 190-196 (2004).
100. Aza-Blanc, P. et al. Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening. Mol. Cell 12, 627-637 (2003).
101. Gorre, M. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293, 876-880 (2001).
102. Shah, N. P. et al. L. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell 2, 117-125 (2002).
103. Jonkers, J. & Berns, A. Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6, 535-538 (2004).
104. Bailey, S. N., Sabatini, D. M. & Stockwell, B. R. Microarrays of small molecules embedded in biodegradable polymers for use in mammalian cell-based screens. Proc. Natl Acad. Sci. USA 101, 16144-16149 (2004).
105. Wheeler, D. B. et al. RNAi living-cell microarrays for loss-of-function screens in Drosophila melanogaster cells. Nature Methods 1, 127-132 (2004).
106. Ooi, S. L., Shoemaker, D. D. & Boeke, J. D. DNA helicase gene interaction network defined using synthetic lethality analyzed by microarray. Nature Genet. 35, 277-286 (2003). Describes the use of DNA bar codes coupled with oligonucleotide microarrays to conduct synthetic lethal assays in yeast.
107. Shoemaker, D. D., Lashkari, D. A., Morris, D., Mittmann, M. & Davis, R. W. Quantitative phenotypic analysis of yeast deletion mutants using a highly parallel molecular barcoding strategy. Nature Genet. 14, 450-456 (1996).
108. Winzeler, E. A. et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 285, 901-906 (1999).
109. Eason, R. G. et al. Characterization of synthetic DNA bar codes in Saccharomyces cerevisiae gene-deletion strains. Proc. Natl Acad. Sci. USA 101, 11046-11051 (2004).
110. Hensel, M. et al. Simultaneous identification of bacterial virulence genes by negative selection. Science 269, 400-403 (1995).