Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?

Abstract

The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field.

Key points

  • The first synthetic lethal therapy (poly(ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1-mutant or BRCA2-mutant ovarian and breast cancers) has been approved for clinical use.

  • Cancer-specific alterations in multiple pathways could, in principle, be targeted using synthetic lethality.

  • Attention will need to be paid to the robustness of synthetic lethal effects observed in preclinical models if the optimal level of translation to clinical benefit is to be achieved.

  • New technology (such as CRISPR–Cas9 mutagenesis) and conceptual advances will speed the discovery of new clinically applicable synthetic lethal interactions.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Parallel pathway-based synthetic lethality.

Adapted from ref.27, Macmillan Publishers Limited.

Fig. 2: Multiple component pathway-based synthetic lethality.
Fig. 3: Paralogue-based synthetic lethality.

Adapted from ref.132, Macmillan Publishers Limited.

Fig. 4: Collateral synthetic lethality via loss of genetic material.
Fig. 5: Collateral synthetic lethality via complex collapse.

Similar content being viewed by others

References

  1. Bridges, C. The origin of variations in sexual and sex-limited characters. Am. Nat. 56, 51–63 (1922).

    Article  Google Scholar 

  2. Dobzhansky, T. Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics 31, 269–290 (1946).

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Ashworth, A., Lord, C. J. & Reis-Filho, J. S. Genetic interactions in cancer progression and treatment. Cell 145, 30–38 (2011).

    Article  PubMed  CAS  Google Scholar 

  4. 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).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Brummelkamp, T. R. & Bernards, R. New tools for functional mammalian cancer genetics. Nat. Rev. Cancer 3, 781–789 (2003).

    Article  PubMed  CAS  Google Scholar 

  7. Rancati, G., Moffat, J., Typas, A. & Pavelka, N. Emerging and evolving concepts in gene essentiality. Nat. Rev. Genet. 19, 34–49 (2018).

    Article  PubMed  CAS  Google Scholar 

  8. Tischler, J., Lehner, B. & Fraser, A. G. Evolutionary plasticity of genetic interaction networks. Nat. Genet. 40, 390–391 (2008).

    Article  PubMed  CAS  Google Scholar 

  9. Muller, F. L., Aquilanti, E. A. & DePinho, R. A. Collateral lethality: a new therapeutic strategy in oncology. Trends Cancer 1, 161–173 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Muller, F. L. et al. Passenger deletions generate therapeutic vulnerabilities in cancer. Nature 488, 337–342 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).

    Article  PubMed  CAS  Google Scholar 

  13. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  PubMed  CAS  Google Scholar 

  14. 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  PubMed  CAS  Google Scholar 

  15. 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).

    Article  PubMed  CAS  Google Scholar 

  16. 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).

    Article  PubMed  CAS  Google Scholar 

  17. Lord, C. J. & Ashworth, A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat. Med. 19, 1381–1388 (2013).

    Article  PubMed  CAS  Google Scholar 

  18. Drean, A. et al. Modeling therapy resistance in BRCA1/2-mutant cancers. Mol. Cancer Ther. 16, 2022–2034 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Drean, A., Lord, C. J. & Ashworth, A. PARP inhibitor combination therapy. Crit. Rev. Oncol. Hematol. 108, 73–85 (2016).

    Article  PubMed  Google Scholar 

  20. Tong, A. H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364–2368 (2001).

    Article  PubMed  CAS  Google Scholar 

  21. Tong, A. H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808–813 (2004).

    Article  PubMed  CAS  Google Scholar 

  22. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

    Article  PubMed  CAS  Google Scholar 

  23. McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).

    Article  PubMed  CAS  Google Scholar 

  24. Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

    Article  CAS  Google Scholar 

  27. Ceccaldi, R. et al. Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair. Nature 518, 258–262 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Mateos-Gomez, P. A. et al. Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination. Nature 518, 254–257 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Murfuni, I. et al. Survival of the replication checkpoint deficient cells requires MUS81-RAD52 function. PLOS Genet. 9, e1003910 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Cramer-Morales, K. et al. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood 122, 1293–1304 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 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 

  32. Lok, B. H. et al. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer. Clin. Cancer Res. 23, 523–535 (2017).

    Article  PubMed  CAS  Google Scholar 

  33. Hengel, S. R., Spies, M. A. & Spies, M. Small-molecule inhibitors targeting DNA repair and DNA repair deficiency in research and cancer therapy. Cell Chem. Biol. 24, 1101–1119 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Lai, X. et al. MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells. Nat. Commun. 8, 15983 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Garaycoechea, J. I. et al. Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells. Nature 553, 171–177 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Tacconi, E. M. et al. BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Mol. Med. 9, 1398–1414 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Mohni, K. N., Kavanaugh, G. M. & Cortez, D. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Cancer Res. 74, 2835–2845 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kwok, M. et al. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway. Lancet 385 (Suppl. 1), 58 (2015).

    Article  PubMed  Google Scholar 

  39. Williamson, C. T. et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A. Nat. Commun. 7, 13837 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Brown, J. S., O’Carrigan, B., Jackson, S. P. & Yap, T. A. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov. 7, 20–37 (2017).

    Article  PubMed  CAS  Google Scholar 

  41. McManus, K. J., Barrett, I. J., Nouhi, Y. & Hieter, P. Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing. Proc. Natl Acad. Sci. USA 106, 3276–3281 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Pfister, S. X. & Ashworth, A. Marked for death: targeting epigenetic changes in cancer. Nat. Rev. Drug Discov. 16, 241–263 (2017).

    Article  PubMed  CAS  Google Scholar 

  43. Wang, X. et al. Oncogenesis caused by loss of the SNF5 tumor suppressor is dependant on the activity of BRG1, the ATPase of the SWI/SNF chromatin remodelling complex. Cancer Res. 69, 8094–8101 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Hoffman, G. R. et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc. Natl Acad. Sci. USA 111, 3128–3133 (2014).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Oike, T. et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 73, 5508–5518 (2013).

    Article  PubMed  CAS  Google Scholar 

  46. Orvis, T. et al. BRG1/SMARCA4 inactivation promotes non-small cell lung cancer aggressiveness by altering chromatin organization. Cancer Res. 74, 6486–6498 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Wilson, B. G. et al. Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation. Mol. Cell. Biol. 34, 1136–1144 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Kadoch, C. & Crabtree, G. R. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci. Adv. 1, e1500447 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Kim, K. H. et al. SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat. Med. 21, 1491–1496 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Bitler, B. G. et al. Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers. Nat. Med. 21, 231–238 (2015).

    Article  PubMed  CAS  Google Scholar 

  51. Januario, T. et al. PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors. Proc. Natl Acad. Sci. USA 114, 12249–12254 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. DeLair, D. F. et al. The genetic landscape of endometrial clear cell carcinomas. J. Pathol. 243, 230–241 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Fujimoto, A. et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat. Genet. 44, 760–764 (2012).

    Article  PubMed  CAS  Google Scholar 

  54. Rokutan, H. et al. Comprehensive mutation profiling of mucinous gastric carcinoma. J. Pathol. 240, 137–148 (2016).

    Article  PubMed  CAS  Google Scholar 

  55. Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Helming, K. C. et al. ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat. Med. 20, 251–254 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Shen, J. et al. ARID1A deficiency impairs the DNA damage checkpoint and sensitizes cells to PARP inhibitors. Cancer Discov. 5, 752–767 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Samartzis, E. P. et al. Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget 5, 5295–5303 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Miller, R. E. et al. Synthetic lethal targeting of ARID1A-mutant ovarian clear cell tumors with dasatinib. Mol. Cancer Ther. 15, 1472–1484 (2016).

    Article  PubMed  CAS  Google Scholar 

  60. Bitler, B. G. et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat. Cell Biol. 19, 962–973 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Chantalat, S. et al. Histone H3 trimethylation at lysine 36 is associated with constitutive and facultative heterochromatin. Genome Res. 21, 1426–1437 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Pfister, S. X. et al. Inhibiting WEE1 selectively kills histone H3K36me3-deficient cancers by dNTP starvation. Cancer Cell 28, 557–568 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  66. Frohling, S. & Scholl, C. STK33 kinase is not essential in KRAS-dependent cells—letter. Cancer Res. 71, 7716 (2011).

    Article  PubMed  CAS  Google Scholar 

  67. Downward, J. RAS synthetic lethal screens revisited: still seeking the elusive prize? Clin. Cancer Res. 21, 1802–1809 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Wang, T. et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic Ras. Cell 168, 890–903 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Aguirre, A. J. & Hahn, W. C. Synthetic lethal vulnerabilities in KRAS-mutant cancers. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a031518 (2017).

    Article  Google Scholar 

  70. Grabocka, E., Commisso, C. & Bar-Sagi, D. Molecular pathways: targeting the dependence of mutant RAS cancers on the DNA damage response. Clin. Cancer Res. 21, 1243–1247 (2015).

    Article  PubMed  CAS  Google Scholar 

  71. 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  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Dietlein, F. et al. A synergistic interaction between Chk1- and MK2 inhibitors in KRAS-mutant cancer. Cell 162, 146–159 (2015).

    Article  PubMed  CAS  Google Scholar 

  74. De Raedt, T. et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 20, 400–413 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Kumar, M. S. et al. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149, 642–655 (2012).

    Article  PubMed  CAS  Google Scholar 

  76. Steckel, M. et al. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res. 22, 1227–1245 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Zhao, D. et al. Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer. Nature 542, 484–488 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Frezza, C. et al. Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase. Nature 477, 225–228 (2011).

    Article  PubMed  CAS  Google Scholar 

  79. Gill, A. J. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology 72, 106–116 (2018).

    Article  PubMed  Google Scholar 

  80. Cardaci, S. et al. Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol. 17, 1317–1326 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Dang, L. & Su, S. M. Isocitrate dehydrogenase mutation and (R)-2-hydroxyglutarate: from basic discovery to therapeutics development. Annu. Rev. Biochem. 86, 305–331 (2017).

    Article  PubMed  CAS  Google Scholar 

  82. Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Sulkowski, P. L. et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl Med. 9, eaal2463 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Molenaar, R. J. et al. IDH1/2 mutations sensitize acute myeloid leukemia to PARP inhibition and this is reversed by IDH1/2-mutant inhibitors. Clin. Cancer Res. 24, 1705–1715 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Chan, S. M. et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat. Med. 21, 178–184 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Karpel-Massler, G. et al. Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL. Nat. Commun. 8, 1067 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Kaelin, W. G. in Kidney Cancer: Principles and Practice (eds Lara, P. N. & Jonasch, E.) 31–57 (Springer International Publishing, 2015).

  88. Chakraborty, A. A. HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1histone methyltransferase. Sci. Transl Med. 9, eaal5272 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Chan, D. A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl Med. 3, 94ra70 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  90. Thompson, J. M. et al. Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma. Oncogene 36, 1080–1089 (2017).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).

    Article  PubMed  CAS  Google Scholar 

  93. Marjon, K. et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep. 15, 574–587 (2016).

    Article  PubMed  CAS  Google Scholar 

  94. Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Nobori, T. et al. Absence of methylthioadenosine phosphorylase in human gliomas. Cancer Res. 51, 3193–3197 (1991).

    PubMed  CAS  Google Scholar 

  96. Dey, P. et al. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer. Nature 542, 119–123 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Dang, C. V. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb. Perspect. Med. 3, a014217 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Whitfield, J. R., Beaulieu, M. E. & Soucek, L. Strategies to inhibit Myc and their clinical applicability. Front. Cell Dev. Biol. 5, 10 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  99. Toyoshima, M. et al. Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc. Natl Acad. Sci. USA 109, 9545–9550 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Campaner, S. et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat. Cell Biol. 12, 54–59 (2010).

    Article  PubMed  CAS  Google Scholar 

  101. Goga, A., Yang, D., Tward, A. D., Morgan, D. O. & Bishop, J. M. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat. Med. 13, 820–827 (2007).

    Article  PubMed  CAS  Google Scholar 

  102. Wang, Y., Miao, Z. H., Pommier, Y., Kawasaki, E. S. & Player, A. Characterization of mismatch and high-signal intensity probes associated with Affymetrix genechips. Bioinformatics 23, 2088–2095 (2007).

    Article  PubMed  CAS  Google Scholar 

  103. Kessler, J. D. et al. A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335, 348–353 (2012).

    Article  PubMed  CAS  Google Scholar 

  104. Horiuchi, D. et al. PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat. Med. 22, 1321–1329 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Poortinga, G., Quinn, L. M. & Hannan, R. D. Targeting RNA polymerase I to treat MYC-driven cancer. Oncogene 34, 403–412 (2015).

    Article  PubMed  CAS  Google Scholar 

  106. Koh, C. M., Sabo, A. & Guccione, E. Targeting MYC in cancer therapy: RNA processing offers new opportunities. Bioessays 38, 266–275 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Camarda, R. et al. Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat. Med. 22, 427–432 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Gordon, G. M. & Du, W. Targeting Rb inactivation in cancers by synthetic lethality. Am. J. Cancer Res. 1, 773–786 (2011).

    PubMed  PubMed Central  Google Scholar 

  109. Buchkovich, K., Duffy, L. A. & Harlow, E. The retinoblastoma protein is phosphorylated during specific phases of the cell cycle. Cell 58, 1097–1105 (1989).

    Article  PubMed  CAS  Google Scholar 

  110. Chen, P. L., Scully, P., Shew, J. Y., Wang, J. Y. & Lee, W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58, 1193–1198 (1989).

    Article  PubMed  CAS  Google Scholar 

  111. Xiao, H. & Goodrich, D. W. The retinoblastoma tumor suppressor protein is required for efficient processing and repair of trapped topoisomerase II-DNA-cleavable complexes. Oncogene 24, 8105–8113 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Li, B., Gordon, G. M., Du, C. H., Xu, J. & Du, W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 17, 469–480 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Zhang, T. et al. Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities. PLOS Genet. 10, e1004357 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. McDonald, E. R. III et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170, 577–592 (2017).

    Article  PubMed  CAS  Google Scholar 

  116. Bertoli, C., Herlihy, A. E., Pennycook, B. R., Kriston-Vizi, J. & de Bruin, R. A. M. Sustained E2F-dependent transcription is a key mechanism to prevent replication-stress-induced DNA damage. Cell Rep. 15, 1412–1422 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Pickering, M. T. & Kowalik, T. F. Rb inactivation leads to E2F1-mediated DNA double-strand break accumulation. Oncogene 25, 746–755 (2006).

    Article  PubMed  CAS  Google Scholar 

  118. Nittner, D. et al. Synthetic lethality between Rb, p53 and Dicer or miR-17-92 in retinal progenitors suppresses retinoblastoma formation. Nat. Cell Biol. 14, 958–965 (2012).

    Article  PubMed  CAS  Google Scholar 

  119. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    Article  PubMed  CAS  Google Scholar 

  120. Reinhardt, H. C. & Schumacher, B. The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet. 28, 128–136 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Gurpinar, E. & Vousden, K. H. Hitting cancers’ weak spots: vulnerabilities imposed by p53 mutation. Trends Cell Biol. 25, 486–495 (2015).

    Article  PubMed  CAS  Google Scholar 

  122. Marcotte, R. et al. Essential gene profiles in breast, pancreatic, and ovarian cancer cells. Cancer Discov. 2, 172–189 (2012).

    Article  PubMed  CAS  Google Scholar 

  123. Campbell, J. et al. Large-scale profiling of kinase dependencies in cancer cell lines. Cell Rep. 14, 2490–2501 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Meyers, R. M. et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat. Genet. 49, 1779–1784 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Ryan, C. J., Kennedy, S., Bajrami, I., Matallanas, D. & Lord, C. J. A. Compendium of co-regulated protein complexes in breast cancer reveals collateral loss events. Cell Syst. 5, 399–409.e5 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Kampmann, M. CRISPRi and CRISPRa screens in mammalian cells for precision biology and medicine. ACS Chem Biol. 13, 406–416 (2018).

    Article  PubMed  CAS  Google Scholar 

  127. Dixit, A. et al. Perturb-seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens. Cell 167, 1853–1866.e17 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Liu, H. et al. Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple negative breast cancer. Cancer Discov. 8, 354–369 (2018).

    Article  PubMed  CAS  Google Scholar 

  129. Palmer, A. C. & Sorger, P. K. Combination cancer therapy can confer benefit via patient-to-patient variability without drug additivity or synergy. Cell 171, 1678–1691 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  130. Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

    Article  PubMed  CAS  Google Scholar 

  131. Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells clinical update. Nat. Rev. Clin. Oncol. 12, 445–464 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nat. Rev. Cancer 11, 481–492 (2011).

    Article  PubMed  CAS  Google Scholar 

  133. Mora, J. et al. Comprehensive analysis of the 9p21 region in neuroblastoma suggests a role for genes mapping to 9p21–23 in the biology of favourable stage 4 tumours. Brit. J. Cancer 91, 1112–1118 (2004).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  134. Ledermann, J. A. et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 17, 1579–1589 (2016).

    Article  PubMed  CAS  Google Scholar 

  135. Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

    Article  PubMed  CAS  Google Scholar 

  136. Swisher, E. M. et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 18, 75–87 (2017).

    Article  PubMed  CAS  Google Scholar 

  137. Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

A.A. acknowledges financial support from the Susan G. Komen for the Cure organization, the Breast Cancer Research Foundation and the BRCA Foundation. C.J.L. acknowledges financial support from Cancer Research UK and Breast Cancer Now.

Author information

Authors and Affiliations

Authors

Contributions

Both authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding authors

Correspondence to Alan Ashworth or Christopher J. Lord.

Ethics declarations

Competing interests

A.A. is or has been a consultant of AtlasMDX, Bluestar, Driver, Genentech, Pfizer, Prolynx, Sun Pharma and Third Rock Ventures; has received research support from Sun Pharma; is the co-founder of Tango Therapeutics; and holds patents on the use of poly(ADP-ribose) polymerase (PARP) inhibitors jointly with AstraZeneca, from which he has benefited financially (and may do so in the future) through the Institute of Cancer Research Rewards to Inventors scheme. C.J.L. is or has been a consultant of AstraZeneca, GLG, Guidepoint, Sun Pharma, Third Rock Ventures and Vertex; has received research support from AstraZeneca and Merck KGaA; and holds patents on the use of DNA repair inhibitors and stands to gain from their use as part of the Institute of Cancer Research Rewards to Inventors scheme.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Achilles: https://portals.broadinstitute.org/achilles

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ashworth, A., Lord, C.J. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?. Nat Rev Clin Oncol 15, 564–576 (2018). https://doi.org/10.1038/s41571-018-0055-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-018-0055-6

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer