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  • Review Article
  • Published:

Harnessing synthetic lethal interactions in anticancer drug discovery

Nature Reviews Drug Discovery volume 10, pages 351–364 (2011)Cite this article

Subjects

Key Points

  • A primary goal of modern cancer drug development is the identification of targeted therapeutics that specifically kill tumour cells while leaving normal healthy cells unharmed.

  • Synthetic lethality began as a description of genetic interactions that were observed in model organisms, but it is rapidly growing into a major strategy in the search for the next generation of targeted cancer therapies.

  • Synthetic lethality is based on the genetic interaction between two genes. Inhibition of either gene alone has no effect on viability, but the combined inhibition of the two genes results in cell death.

  • Cancer cells are frequently distinguished from normal cells by defects in specific genes that drive their growth and metastasis, and so the identification of genes or drugs that have a synthetic lethal interaction with cancer-promoting genes represents a compelling approach for the development of targeted therapies.

  • The advent of RNA interference technologies allows whole-genome screening to uncover novel genetic interactions, whereas screening of small-molecule libraries can reveal novel lead agents for cancers with specific genetic mutations. Mutations in both gain-of-function oncogenes and loss-of-function tumour suppressor genes can be targeted.

  • Conditional synthetic lethality exploits changes in gene expression that are induced by the tumour microenvironment, leading to an additional layer of specificity.

  • DNA repair genes that are mutated in some cancers have been the most common targets of synthetic lethality studies so far, and these studies are the most clinically developed. Among the findings are the selective sensitivity of BRCA-deficient breast cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors and the importance of certain DNA polymerases for the survival of colorectal carcinomas that are defective in DNA mismatch repair proteins. PARP inhibitors have demonstrated clinical efficacy in BRCA-mutant breast and ovarian tumours.

  • This Review explores how synthetic lethality screening can be used to identify new interactions and molecules for the treatment of cancer.

Abstract

Unique features of tumours that can be exploited by targeted therapies are a key focus of current cancer research. One such approach is known as synthetic lethality screening, which involves searching for genetic interactions of two mutations whereby the presence of either mutation alone has no effect on cell viability but the combination of the two mutations results in cell death. The presence of one of these mutations in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Here, we summarize strategies that can be used to identify synthetic lethal interactions for anticancer drug discovery, describe examples of such interactions that are currently being investigated in preclinical and clinical studies of targeted anticancer therapies, and discuss the challenges of realizing the full potential of such therapies.

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Figure 1: Synthetic lethality.
Figure 2: Mammalian synthetic lethality screens for anticancer efficacy.
Figure 3: Example of a conditional synthetic lethality opportunity.

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References

  1. Druker, B. J. Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Hellman, S. & Vokes, E. E. Advancing current treatments for cancer. Sci. Am. 275, 118–123 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Oliff, A., Gibbs, J. B. & McCormick, F. New molecular targets for cancer therapy. Sci. Am. 275, 144–149 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Hynes, N. E. & Lane, H. A. ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Rev. Cancer 5, 341–354 (2005).

    Article  CAS  Google Scholar 

  5. Buchdunger, E. et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 56, 100–104 (1996).

    CAS  PubMed  Google Scholar 

  6. Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Druker, B. J. et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells. Nature Med. 2, 561–566 (1996). This preclinical study identified imatinib as a compound that was capable of interfering with tyrosine kinase activity of BCR–ABL in cell lines, primary tumour cells and in xenograft tumours.

    Article  CAS  PubMed  Google Scholar 

  8. Talpaz, M. et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N. Engl. J. Med. 354, 2531–2541 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Pollack, V. A. et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. J. Pharmacol. Exp. Ther. 291, 739–748 (1999).

    CAS  PubMed  Google Scholar 

  11. Ansari, J., Palmer, D. H., Rea, D. W. & Hussain, S. A. Role of tyrosine kinase inhibitors in lung cancer. Anticancer Agents Med. Chem. 9, 569–575 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Shepherd, F. A. et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Ng, S. S., Tsao, M. S., Nicklee, T. & Hedley, D. W. Effects of the epidermal growth factor receptor inhibitor OSI-774, Tarceva, on downstream signaling pathways and apoptosis in human pancreatic adenocarcinoma. Mol. Cancer Ther. 1, 777–783 (2002).

    CAS  PubMed  Google Scholar 

  15. Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Ahmad, T. & Eisen, T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin. Cancer Res. 10, 6388S–6392S (2004).

  17. Motzer, R. J. et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 24, 16–24 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Mendel, D. B. et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin. Cancer Res. 9, 327–337 (2003).

    CAS  PubMed  Google Scholar 

  19. Gu, J., Ruppen, M. E. & Cai, P. Lipase-catalyzed regioselective esterification of rapamycin: synthesis of temsirolimus (CCI-779). Org. Lett. 7, 3945–3948 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Sedrani, R., Cottens, S., Kallen, J. & Schuler, W. Chemical modification of rapamycin: the discovery of SDZ RAD. Transplant Proc. 30, 2192–2194 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Motzer, R. J. et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372, 449–456 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Hudes, G. et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356, 2271–2281 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Escudier, B. et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370, 2103–2111 (2007).

    Article  PubMed  Google Scholar 

  24. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 356, 125–134 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Motzer, R. J. et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N. Engl. J. Med. 356, 115–124 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Liu, L. et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66, 11851–11858 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Force, T. & Kolaja, K. L. Cardiotoxicity of kinase inhibitors: the prediction and translation of preclinical models to clinical outcomes. Nature Rev. Drug Discov. 10, 111–126 (2011).

    Article  CAS  Google Scholar 

  29. Janne, P. A., Gray, N. & Settleman, J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nature Rev. Drug Discov. 8, 709–723 (2009).

    Article  CAS  Google Scholar 

  30. Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W. & Friend, S. H. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997). This paper proposed applying classical yeast genetics to discovering novel chemotherapies with a specific focus on DNA repair pathways.

    Article  CAS  PubMed  Google Scholar 

  31. 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). This study describeda synthetic lethality screen in yeast to identify unknown interactions between different genes.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nature Rev. Cancer 5, 689–698 (2005).

    Article  CAS  Google Scholar 

  33. Kaelin, W. G. Jr. Synthetic lethality: a framework for the development of wiser cancer therapeutics. Genome Med. 1, 99 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guarente, L. Synthetic enhancement in gene interaction: a genetic tool come of age. Trends Genet. 9, 362–366 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Hartman, J. L., Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005). One of two papers identifying PARP inhibitors as synthetically lethalto BRCA mutations.

    Article  CAS  PubMed  Google Scholar 

  38. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005). The other paper identifying a genetic interaction between PARP inhibition (repair of single-stranded DNA breaks) and BRCA mutation (which was important for homologous recombinational repair of double-stranded DNA breaks).

    Article  CAS  PubMed  Google Scholar 

  39. Felsher, D. W. & Bishop, J. M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).

    Article  CAS  PubMed  Google Scholar 

  40. Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3, 565–577 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Prochownik, E. V. & Vogt, P. K. Therapeutic targeting of Myc. Genes Cancer 1, 650–659 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Harris, C. C. & Hollstein, M. Clinical implications of the p53 tumor-suppressor gene. N. Engl. J. Med. 329, 1318–1327 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Olivier, M. et al. Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther. 16, 1–12 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Liu, T. C., Hwang, T. H., Bell, J. C. & Kirn, D. H. Translation of targeted oncolytic virotherapeutics from the lab into the clinic, and back again: a high-value iterative loop. Mol. Ther. 16, 1006–1008 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Gien, L. T. & Mackay, H. J. The emerging role of PARP inhibitors in the treatment of epithelial ovarian cancer. J. Oncol. 2010, 151750 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010). This paper demonstrated the use of PARP inhibitors for relapsed or metastatic breast cancer with BRCA mutations.

    Article  CAS  PubMed  Google Scholar 

  47. Audeh, M. W. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376, 245–251 (2010). This paper demonstrated the use of PARP inhibitors for relapsed or metastatic ovarian cancers with BRCA mutations.

    Article  CAS  PubMed  Google Scholar 

  48. Brummelkamp, T. R., Nijman, S. M., Dirac, A. M. & Bernards, R. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature 424, 797–801 (2003). This paper describes one of the first large-scale RNAi library screens.

    Article  CAS  PubMed  Google Scholar 

  49. Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Scholl, C. et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821–834 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Einav, Y. et al. Replication and episomal maintenance of Epstein-Barr virus-based vectors in mouse embryonal fibroblasts enable synthetic lethality screens. Mol. Cancer Ther. 2, 1121–1128 (2003).

    CAS  PubMed  Google Scholar 

  53. 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). This study used episomal gene transfer to circumvent genetic drift of isogenic cell lines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Simons, A. H., 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bindra, R. S. et al. Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol. Cell Biol. 24, 8504–8518 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chan, N. et al. Chronic hypoxia decreases synthesis of homologous recombination proteins to offset chemoresistance and radioresistance. Cancer Res. 68, 605–614 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Chan, N. et al. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res. 70, 8045–8054 (2010). This paper describesa conditional synthetic lethality whereby hypoxia suppresses DNA repair proteins and subsequently makes cells deficient in recombinational repair and, consequently, sensitive to PARP inhibition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen, Y., Cairns, R., Papandreou, I., Koong, A. & Denko, N. C. Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS ONE 4, e7033 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Michelakis, E. D., Webster, L. & Mackey, J. R. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br. J. Cancer 99, 989–994 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Banasik, M. & Ueda, K. Inhibitors and activators of ADP-ribosylation reactions. Mol. Cell. Biochem. 138, 185–197 (1994).

    Article  CAS  PubMed  Google Scholar 

  61. Loh, V. M. Jr et al. Phthalazinones. Part 1: the design and synthesis of a novel series of potent inhibitors of poly(ADP-ribose) polymerase. Bioorg. Med. Chem. Lett. 15, 2235–2238 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Pivazyan, A. D., Birks, E. M., Wood, T. G., Lin, T. S. & Prusoff, W. H. Inhibition of poly(ADP-ribose)polymerase activity by nucleoside analogs of thymidine. Biochem. Pharmacol. 44, 947–953 (1992).

    Article  CAS  PubMed  Google Scholar 

  63. Skalitzky, D. J. et al. Tricyclic benzimidazoles as potent poly(ADP-ribose) polymerase-1 inhibitors. J. Med. Chem. 46, 210–213 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Rouleau, M., Patel, A., Hendzel, M. J., Kaufmann, S. H. & Poirier, G. G. PARP inhibition: PARP1 and beyond. Nature Rev. Cancer 10, 293–301 (2010).

    Article  CAS  Google Scholar 

  65. Hall, J. M. et al. Closing in on a breast cancer gene on chromosome 17q. Am. J. Hum. Genet. 50, 1235–1242 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Casey, G. et al. Functional evidence for a breast cancer growth suppressor gene on chromosome 17. Hum. Mol. Genet. 2, 1921–1927 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Wooster, R. et al. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265, 2088–2090 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Parikh, B. & Advani, S. Pattern of second primary neoplasms following breast cancer. J. Surg. Oncol. 63, 179–182 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. Petermann, E., Keil, C. & Oei, S. L. Importance of poly(ADP-ribose) polymerases in the regulation of DNA-dependent processes. Cell. Mol. Life Sci. 62, 731–738 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Ashworth, A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 26, 3785–3790 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Hutchinson, L. Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nature Rev. Clin. Oncol. 7, 549 (2010).

    Article  Google Scholar 

  73. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nature Rev. Cancer 4, 814–819 (2004).

    Article  CAS  Google Scholar 

  74. Efimova, E. V. et al. Poly(ADP-ribose) polymerase inhibitor induces accelerated senescence in irradiated breast cancer cells and tumors. Cancer Res. 70, 6277–6282 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Loser, D. A. et al. Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair. Mol. Cancer Ther. 9, 1775–1787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bhattacharyya, A., Ear, U. S., Koller, B. H., Weichselbaum, R. R. & Bishop, D. K. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J. Biol. Chem. 275, 23899–23903 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Moynahan, M. E., Cui, T. Y. & Jasin, M. Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 61, 4842–4850 (2001).

    CAS  PubMed  Google Scholar 

  78. Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Kraakman-van der Zwet, M. et al. Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions. Mol. Cell Biol. 22, 669–679 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Evers, B. et al. Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin. Clin. Cancer Res. 14, 3916–3925 (2008).

    Article  CAS  PubMed  Google Scholar 

  81. Rottenberg, S. et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl Acad. Sci. USA 105, 17079–17084 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Fong, P. C. et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J. Clin. Oncol. 28, 2512–2519 (2010).

    Article  CAS  PubMed  Google Scholar 

  83. Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chan, S. L. & Mok, T. PARP inhibition in BRCA-mutated breast and ovarian cancers. Lancet 376, 211–213 (2010).

    Article  PubMed  Google Scholar 

  85. Gottipati, P. et al. Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res. 70, 5389–5398 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Feng, Z. et al. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc. Natl Acad. Sci. USA 108, 686–691 (2011).

    Article  PubMed  Google Scholar 

  87. Willers, H. et al. Utility of DNA repair protein foci for the detection of putative BRCA1 pathway defects in breast cancer biopsies. Mol. Cancer Res. 7, 1304–1309 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Martin, S. A. et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell 17, 235–248 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Martin, S. A., Hewish, M., Sims, D., Lord, C. J. & Ashworth, A. Parallel high throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair deficient cancers. Cancer Res. 71, 1836–1848 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    Article  CAS  PubMed  Google Scholar 

  92. Leach, F. S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).

    Article  CAS  PubMed  Google Scholar 

  93. Strand, M., Prolla, T. A., Liskay, R. M. & Petes, T. D. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365, 274–276 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. Koi, M. et al. Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N′-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 54, 4308–4312 (1994).

    CAS  PubMed  Google Scholar 

  95. Campbell, J. L., Soll, L. & Richardson, C. C. Isolation and partial characterization of a mutant of Escherichia coli deficient in DNA polymerase II. Proc. Natl Acad. Sci. USA 69, 2090–2094 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Matsukage, A. et al. Assignment of the gene for human DNA polymerase β (POLB) to chromosome 8. Jpn J. Cancer Res. 77, 330–333 (1986).

    CAS  PubMed  Google Scholar 

  97. Sobol, R. W. et al. Requirement of mammalian DNA polymerase-β in base-excision repair. Nature 379, 183–186 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Zullo, S. J. et al. Localization by fluorescence in situ hybridization (FISH) of human mitochondrial polymerase γ (POLG) to human chromosome band 15q24→q26, and of mouse mitochondrial polymerase γ (Polg) to mouse chromosome band 7E, with confirmation by direct sequence analysis of bacterial artificial chromosomes (BACs). Cytogenet. Cell Genet. 78, 281–284 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Ropp, P. A. & Copeland, W. C. Cloning and characterization of the human mitochondrial DNA polymerase, DNA polymerase γ. Genomics 36, 449–458 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. Kaelin, W. G. Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nature Rev. Cancer 8, 865–873 (2008).

    Article  CAS  Google Scholar 

  101. Melmon, K. L. & Rosen, S. W. Lindau's disease. Review of the literature and study of a large kindred. Am. J. Med. 36, 595–617 (1964).

    Article  CAS  PubMed  Google Scholar 

  102. Gnarra, J. R. et al. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genet. 7, 85–90 (1994).

    Article  CAS  PubMed  Google Scholar 

  103. Herman, J. G. et al. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc. Natl Acad. Sci. USA 91, 9700–9704 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Young, A. C. et al. Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin. Cancer Res. 15, 7582–7592 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ritchie, A. W. & Chisholm, G. D. The natural history of renal carcinoma. Semin. Oncol. 10, 390–400 (1983).

    CAS  PubMed  Google Scholar 

  106. Motzer, R. J., Russo, P., Nanus, D. M. & Berg, W. J. Renal cell carcinoma. Curr. Probl. Cancer 21, 185–232 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Iliopoulos, O., Kibel, A., Gray, S. & Kaelin, W. G. Jr. Tumour suppression by the human von Hippel-Lindau gene product. Nature Med. 1, 822–826 (1995).

    Article  CAS  PubMed  Google Scholar 

  108. Bommi-Reddy, A. et al. Kinase requirements in human cells: III. Altered kinase requirements in VHL−/− cancer cells detected in a pilot synthetic lethal screen. Proc. Natl Acad. Sci. USA 105, 16484–16489 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Turcotte, S. et al. A molecule targeting VHL-deficient renal cell carcinoma that induces autophagy. Cancer Cell 14, 90–102 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Chan, D. A. & Giaccia, A. J. Targeting cancer cells by synthetic lethality: autophagy and VHL in cancer therapeutics. Cell Cycle 7, 2987–2990 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Turcotte, S. & Giaccia, A. J. Targeting cancer cells through autophagy for anticancer therapy. Curr. Opin. Cell Biol. 22, 246–251 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122–127 (2006). References 113–115 describe synthetic lethal interactions between mTOR inhibitors and mutation of the PTEN tumour suppressor protein.

    Article  CAS  PubMed  Google Scholar 

  116. Kau, T. R. et al. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 4, 463–476 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Dedes, K. J. et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci. Transl. Med. 2, 53ra75 (2010).

  119. McEllin, B. et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 70, 5457–5464 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cho, K. R. & Vogelstein, B. Genetic alterations in the adenoma–carcinoma sequence. Cancer 70, 1727–1731 (1992).

    Article  CAS  PubMed  Google Scholar 

  122. Bommi-Reddy, A. & Kaelin, W. G. Jr. Slaying RAS with a synthetic lethal weapon. Cell Res. 20, 119–121 (2010).

    Article  PubMed  Google Scholar 

  123. Sawyers, C. L. Finding and drugging the vulnerabilities of RAS-dependent cancers. Cell 137, 796–798 (2009).

    Article  CAS  PubMed  Google Scholar 

  124. Torrance, C. J., Agrawal, V., Vogelstein, B. & Kinzler, K. W. Use of isogenic human cancer cells for high-throughput screening and drug discovery. Nature Biotech. 19, 940–945 (2001). This paper describes an isogenic cell synthetic lethality screen to target oncogenic RAS.

    Article  CAS  Google Scholar 

  125. Sarthy, A. V. et al. Survivin depletion preferentially reduces the survival of activated K-Ras-transformed cells. Mol. Cancer Ther. 6, 269–276 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Puyol, M. et al. 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 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Malumbres, M., Pevarello, P., Barbacid, M. & Bischoff, J. R. CDK inhibitors in cancer therapy: what is next? Trends Pharmacol. Sci. 29, 16–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  128. Gilad, O. et al. Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 70, 9693–9702 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Steegmaier, M. et al. BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr. Biol. 17, 316–322 (2007).

    Article  CAS  PubMed  Google Scholar 

  130. Mujica, A. O., Hankeln, T. & Schmidt, E. R. A novel serine/threonine kinase gene, STK33, on human chromosome 11p15.3. Gene 280, 175–181 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Chien, Y. & White, M. A. Characterization of RalB-Sec5-TBK1 function in human oncogenesis. Methods Enzymol. 438, 321–329 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Meylan, E. et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature 462, 104–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 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).

    Article  CAS  PubMed  Google Scholar 

  135. Yagoda, N. et al. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wang, Y. et al. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5, 501–512 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Yang, D. et al. Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc. Natl Acad. Sci. USA 107, 13836–13841 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the following grants from the US National Cancer Institute: NCI-CA-67166 (A.J.G), NCI-CA-88480 (A.J.G) and NCI-CA-123823 (D.A.C). It was also supported by a grant from Action to Cure Kidney Cancer (A.J.G.). We apologize to colleagues whose work we failed to cite.

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  1. Department of Radiation Oncology, University of California, San Francisco, 94143-1331, California, USA

    Denise A. Chan

  2. Department of Radiation Oncology, Stanford University School of Medicine, Stanford, 94305-5152, California, USA

    Amato J. Giaccia

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Correspondence to Amato J. Giaccia.

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Amato J. Giaccia is a founder of Ruga Corporation. Denise A. Chan is a scientific consultant for Ruga Corporation.

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Glossary

Small interfering RNA

(siRNA). A sequence of double-stranded RNA, generally 21 nucleotides in length, which targets specific mRNA sequences for degradation or inhibits translation of specific genes. Synthetic siRNAs can be introduced into a cell by transfection but they are short-lived.

Poly(ADP-ribose) polymerase

(PARP). A family of enzymes that catalyses the conversion of nicotinamide adenine dinucleotide into nicotinamide and polymers of ADP-ribose at glutamic acid residues of nuclear proteins. These enzymes are involved in a variety of cellular processes, notably DNA repair.

Short hairpin RNA

(shRNA). A plasmid or vector-based method for producing stable gene silencing. A promoter drives transcription of a target sequence, which forms a hairpin loop that is processed by the cellular RNA interference machinery, thereby forming small interfering RNAs to silence a particular gene.

Replication fork

The structure formed from the unwinding and breaking of the hydrogen bond of the two strands of DNA during replication. Each individual strand of DNA becomes a template for replication.

Knudson two-hit hypothesis

A model that proposes that cancer is a genetic disease and that successive genetic alterations in both alleles are needed to turn a normal cell into a cancer cell. In spontaneous cancers, two successive rare events must occur but in cases of hereditary susceptibility to cancer, inheritance of a damaged gene followed by a rare event results in mutation.

Clonogenic survival curve

The standard method for determining the effectiveness of a particular treatment on the proliferation of cells. Cells are plated in a tissue culture dish and allowed to attach overnight. The plates are then treated and grown until single cells form colonies, which are then fixed, stained and counted.

Autophagy

A catabolic process that sequesters and recycles cellular components, including organelles and long-lived proteins, in response to diverse stimuli. Autophagosomes form via invagination of the cell membrane, creating double-membrane vesicles. These autophagic vesicles then fuse with lysosomes, creating autophagolysosomes in which the contents of the cell are degraded by acidic lysosomal hydrolases.

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Chan, D., Giaccia, A. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat Rev Drug Discov 10, 351–364 (2011). https://doi.org/10.1038/nrd3374

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