WRN helicase is a synthetic lethal target in microsatellite unstable cancers

Nature

Volumn 568, Issue 7753, 2019, Pages 551-556

  Chan, Edmond M ^a,b   Shibue, Tsukasa ^a   McFarland, James M ^a   Gaeta, Benjamin ^a   Ghandi, Mahmoud ^a   Dumont, Nancy ^a   Gonzalez, Alfredo ^a   McPartlan, Justine S ^a   Li, Tianxia ^b   Zhang, Yanxi ^b   Bin Liu, Jie ^b   Lazaro, Jean Bernard ^b   Gu, Peili ^c   Piett, Cortt G ^d   Apffel, Annie ^a   Ali, Syed O ^a,b   Deasy, Rebecca ^a   Keskula, Paula ^a   Ng, Raymond W S ^a,b   Roberts, Emma A ^b   Reznichenko, Elizaveta ^b   Leung, Lisa ^a   Alimova, Maria ^a   Schenone, Monica ^a   Islam, Mirazul ^a,b   Maruvka, Yosef E ^a,e   Liu, Yang ^a,b   Roper, Jatin ^f   Raghavan, Srivatsan ^a,b   Giannakis, Marios ^a,b   Tseng, Yuen Yi ^a   Nagel, Zachary D ^a,d   D’Andrea, Alan ^b   Root, David E ^a   Boehm, Jesse S ^a   Getz, Gad ^a,e   Chang, Sandy ^c   Golub, Todd R ^a,b,g   Tsherniak, Aviad ^a   Vazquez, Francisca ^a,b   Bass, Adam J ^a,b   more..

^a BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^e MASSACHUSETTS GENERAL HOSPITAL CANCER CENTER   (United States)

^f DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^g HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CRISPR ASSOCIATED ENDONUCLEASE CAS9; CRISPR ASSOCIATED PROTEIN; MESSENGER RNA; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; WERNER SYNDROME ATP DEPENDENT HELICASE; MICROSATELLITE DNA; PROTEIN P53; TP53 PROTEIN, HUMAN; WRN PROTEIN, HUMAN; EXONUCLEASE; RECQ HELICASE;

CELL CYCLE ARREST; CELL LINEAGE; CELL VIABILITY; CORRELATION ANALYSIS; DNA REPAIR; DNA SYNTHESIS; DOUBLE STRANDED DNA BREAK; ENZYME ACTIVITY; FLUORESCENCE IN SITU HYBRIDIZATION; GENE; GENE SEQUENCE; GENE SILENCING; GENETIC SCREENING; HUMAN; IMMUNE RESPONSE; IMMUNOBLOTTING; IMMUNOFLUORESCENCE; LETTER; MALIGNANT NEOPLASM; MICROSATELLITE INSTABILITY; MISMATCH REPAIR; MLH1 GENE; MMR GENE; MSH2 GENE; MSH6 GENE; NONHUMAN; NUCLEOLUS; PHENOTYPE; PMS2 GENE; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN DEPLETION; PROTEIN LOCALIZATION; PROTEIN PHOSPHORYLATION; RNA INTERFERENCE; APOPTOSIS; BIOLOGICAL MODEL; CELL CYCLE CHECKPOINT; CRISPR CAS SYSTEM; GENETICS; LETHAL MUTATION; METABOLISM; NEOPLASM; PATHOLOGY; TUMOR CELL LINE; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; CANCER GENETICS; CANCER MODEL; CANCER THERAPY; CELL DEATH; CONTROLLED STUDY; GENE KNOCKOUT; HOMOLOGOUS RECOMBINATION; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR GENETICS; SYNTHETIC LETHALITY;

APOPTOSIS; CELL CYCLE CHECKPOINTS; CELL LINE, TUMOR; CRISPR-CAS SYSTEMS; DNA BREAKS, DOUBLE-STRANDED; HUMANS; MICROSATELLITE INSTABILITY; MICROSATELLITE REPEATS; MODELS, GENETIC; NEOPLASMS; RNA INTERFERENCE; SYNTHETIC LETHAL MUTATIONS; TUMOR SUPPRESSOR PROTEIN P53; WERNER SYNDROME HELICASE;

EID: 85064214826     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/s41586-019-1102-x     Document Type: Article

References (50)

1. Chan, D. A. & Giaccia, A. J. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov. 10, 351–364 (2011).
2. Ivy, S. P., de Bono, J. & Kohn, E. C. The ‘Pushmi–Pullyu’ of DNA repair: clinical synthetic lethality. Trends Cancer 2, 646–656 (2016).
3. Brown, J. S., Kaye, S. B. & Yap, T. A. PARP inhibitors: the race is on. Br. J. Cancer 114, 713–715 (2016).
4. Kim, T. M., Laird, P. W. & Park, P. J. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858–868 (2013).
5. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
6. Kunitomi, H. et al. New use of microsatellite instability analysis in endometrial cancer. Oncol. Lett. 14, 3297–3301 (2017).
7. Pal, T., Permuth-Wey, J., Kumar, A. & Sellers, T. A. Systematic review and meta-analysis of ovarian cancers: estimation of microsatellite-high frequency and characterization of mismatch repair deficient tumor histology. Clin. Cancer Res. 14, 6847–6854 (2008).
8. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
9. Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).
10. 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).
11. 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).
12. Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
13. Iorio, F. et al. A landscape of pharmacogenomic interactions in cancer. Cell 166, 740–754 (2016).
14. Swanson, C., Saintigny, Y., Emond, M. J. & Monnat, R. J. Jr. The Werner syndrome protein has separable recombination and survival functions. DNA Repair 3, 475–482 (2004).
15. Rossi, M. L., Ghosh, A. K. & Bohr, V. A. Roles of Werner syndrome protein in protection of genome integrity. DNA Repair 9, 331–344 (2010).
16. Buehler, E., Chen, Y. C. & Martin, S. C911: a bench-level control for sequence specific siRNA off-target effects. PLoS ONE 7, e51942 (2012).
17. Loughery, J., Cox, M., Smith, L. M. & Meek, D. W. Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic Acids Res. 42, 7666–7680 (2014).
18. Shiloh, Y. & Ziv, Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14, 197–210 (2013).
19. Nowsheen, S. & Yang, E. S. The intersection between DNA damage response and cell death pathways. Exp. Oncol. 34, 243–254 (2012).
20. Bendtsen, K. M. et al. Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli. Eur. Biophys. J. 43, 509–516 (2014).
21. Billingsley, C. C. et al. Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing. Cancer 121, 386–394 (2015).
22. Haugen, A. C. et al. Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer. Cancer Res. 68, 8465–8472 (2008).
23. Sidorova, J. M. Roles of the Werner syndrome RecQ helicase in DNA replication. DNA Repair 7, 1776–1786 (2008).
24. Spies, M. & Fishel, R. Mismatch repair during homologous and homeologous recombination. Cold Spring Harb. Perspect. Biol. 7, a022657 (2015).
25. Opresko, P. L., Sowd, G. & Wang, H. The Werner syndrome helicase/exonuclease processes mobile D-loops through branch migration and degradation. PLoS ONE 4, e4825 (2009).
26. Myung, K., Datta, A., Chen, C. & Kolodner, R. D. SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Nat. Genet. 27, 113–116 (2001).
27. Aggarwal, M., Banerjee, T., Sommers, J. A. & Brosh, R. M. Jr. Targeting an Achilles’ heel of cancer with a WRN helicase inhibitor. Cell Cycle 12, 3329–3335 (2013).
28. Lebel, M. & Monnat, R. J. Jr. Werner syndrome (WRN) gene variants and their association with altered function and age-associated diseases. Ageing Res. Rev. 41, 82–97 (2018).
29. Behan, F. M. et al. Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens. Nature https://doi.org/10.1038/s41586-019-1103-9 (2019).
30. Tsherniak, A. et al. Defining a cancer dependency map. Cell 170, 564–576 (2017).
31. Broad DepMap. DepMap Achilles 18Q4 public. FigShare version 2 https://figshare.com/articles/DepMap_Achilles_18Q4_public/7270880 (2018).
32. McFarland, J. M. et al. Improved estimation of cancer dependencies from large-scale RNAi screens using model-based normalization and data integration. Nat. Commun. 9, 4610 (2018).
33. Cancer Data Science. DEMETER2 data. FigShare version 5 https://figshare.com/articles/DEMETER2_data/6025238/5 (2018).
34. Cancer Cell Line Encyclopedia Consortium. Pharmacogenomic agreement between two cancer cell line data sets. Nature 528, 84–87 (2015).
35. Giacomelli, A. O. et al. Mutational processes shape the landscape of TP53 mutations in human cancer. Nat. Genet. 50, 1381–1387 (2018).
36. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
37. Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).
38. Robinson, M. D. & Oshlack, A. A scaling normalization method for differential expression analysis of RNA-seq data. Genome Biol. 11, R25 (2010).
39. Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
40. Law, C. W., Chen, Y., Shi, W. & Smyth, G. K. voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 15, R29 (2014).
41. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).
42. Sergushichev, A. A. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. Preprint at https://www.biorxiv.org/content/10.1101/060012v1 (2016).
43. Liberzon, A., et al. The molecular signatures database hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
44. Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).
45. Shibue, T., Brooks, M. W., Inan, M. F., Reinhardt, F. & Weinberg, R. A. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov. 2, 706–721 (2012).
46. Lenth, R. V. Least-squares means: the R package Ismeans. J. Stat. Softw. 69, 1–33 (2016).
47. Dejmek, J., Iglehart, J. D. & Lazaro, J. B. DNA-dependent protein kinase (DNA-PK)-dependent cisplatin-induced loss of nucleolar facilitator of chromatin transcription (FACT) and regulation of cisplatin sensitivity by DNA-PK and FACT. Mol. Cancer Res. 7, 581–591 (2009).
48. Bates, D. et al. Fitting linear mixed-effects models using lme4. J. Stat. Softw. 67, 1–48 (2015).
49. Nagel, Z. D. et al. Multiplexed DNA repair assays for multiple lesions and multiple doses via transcription inhibition and transcriptional mutagenesis. Proc. Natl Acad. Sci. USA 111, E1823–E1832 (2014).
50. Cancer Data Science. DepMap Datasets for WRN manuscript. FigShare https://figshare.com/articles/DepMap_Datasets_for_WRN_manuscript/7712756 (2019).