SpringerLink
Log in

Exploring the DNA damage response pathway for synthetic lethality

  • Review Article
  • Published:
Genome Instability & Disease Aims and scope Submit manuscript

Abstract

Synthetic lethality (SL) describes a situation in which the occurrence of one genetic event maintains cell viability, whereas the co-occurrence of two genetic events lead to cell death. DNA damage response (DDR) pathway represents the most attractive synthetic lethality targets, since genomic instability is a hallmark of cancers due to the accumulation of DNA mutation during the process of DNA damage response. The definition of synthetic lethality will help to target cancer cells precisely and tackle the undruggable targets. In recent years, the success of DNA damage response inhibitors in cancer treatment highlights the potential of this approach. In this review, we will highlight the concept of synthetic lethality, strategy as well as the most recent development in this area.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available within the submitted article.

References

  • Adames, N. R., Gallegos, J. E., & Peccoud, J. (2019). Yeast genetic interaction screens in the age of CRISPR/Cas. Current Genetics, 65(2), 307–327.

    Article  CAS  PubMed  Google Scholar 

  • Ahlskog, J. K., Larsen, B. D., Achanta, K., & Sørensen, C. S. (2016). ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO Reports, 17(5), 671–681.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Álvarez-Quilón, A., et al. (2020). Endogenous DNA 3’ Blocks Are Vulnerabilities for BRCA1 and BRCA2 deficiency and are reversed by the APE2 nuclease. Molecular Cell, 78(6), 1152-1165.e1158.

    Article  PubMed  PubMed Central  Google Scholar 

  • Anastasia, A., et al. (2022). The DNA-PK Inhibitor AZD7648 Sensitizes patient-derived ovarian cancer xenografts to pegylated liposomal doxorubicin and olaparib preventing abdominal metastases. Molecular Cancer Therapeutics, 21(4), 555–567.

    Article  CAS  PubMed  Google Scholar 

  • Audeh, M. W., et al. (2010). Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet (london, England), 376(9737), 245–251.

    Article  CAS  PubMed  Google Scholar 

  • Bajrami, I., et al. (2014). Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity. Cancer Research, 74(1), 287–297.

    Article  CAS  PubMed  Google Scholar 

  • Banerjee, S., et al. (2021). Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Oncology, 22(12), 1721–1731.

    Article  CAS  PubMed  Google Scholar 

  • Barazas, M., et al. (2018). The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-Deficient cells. Cell Reports, 23(7), 2107–2118.

    Article  CAS  PubMed  Google Scholar 

  • Barretina, J., et al. (2012). The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature, 483(7391), 603–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beebe, J., & Zhang, J. T. (2019). CC-115, a dual mammalian target of Rapamycin/DNA-Dependent Protein kinase inhibitor in clinical trial, is a substrate of ATP-Binding Cassette G2, a risk factor for CC-115 resistance. The Journal of Pharmacology and Experimental Therapeutics, 371(2), 320–326.

    Article  CAS  PubMed  Google Scholar 

  • Behan, F. M., et al. (2019). Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature, 568(7753), 511–516.

    Article  CAS  PubMed  Google Scholar 

  • Benfatto, S., et al. (2021). Uncovering cancer vulnerabilities by machine learning prediction of synthetic lethality. Molecular Cancer, 20(1), 111.

    Article  PubMed  PubMed Central  Google Scholar 

  • Blosser, W. D., et al. (2020). A pan-cancer transcriptome analysis identifies replication fork and innate immunity genes as modifiers of response to the CHK1 inhibitor prexasertib. Oncotarget, 11(3), 216–236.

    Article  PubMed  PubMed Central  Google Scholar 

  • Blunt, T., et al. (1995). Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell, 80(5), 813–823.

    Article  CAS  PubMed  Google Scholar 

  • Bolck, H. A., et al. (2022). RNAi screening uncovers a synthetic sick interaction between CtIP and the BARD1 tumor suppressor. Cells, 11(4), 643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouwman, P., et al. (2010). 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nature Structural & Molecular Biology, 17(6), 688–695.

    Article  CAS  Google Scholar 

  • Bradbury, A., Hall, S., Curtin, N., & Drew, Y. (2020). Targeting ATR as cancer therapy: A new era for synthetic lethality and synergistic combinations? Pharmacology & Therapeutics, 207, 107450.

    Article  CAS  Google Scholar 

  • Bridges, C. B. (1922). The origin of variations ins sexual and sex-limited characters. The American Naturalist, 56, 51–63.

    Article  Google Scholar 

  • Brown, J. S., O’Carrigan, B., Jackson, S. P., & Yap, T. A. (2017). Targeting DNA repair in cancer: Beyond PARP inhibitors. Cancer Discovery, 7(1), 20–37.

    Article  CAS  PubMed  Google Scholar 

  • Bryant, H. E., et al. (2005). Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 434(7035), 913–917.

    Article  CAS  PubMed  Google Scholar 

  • Bunting, S. F., et al. (2010). 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell, 141(2), 243–254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Callen, E., et al. (2020). 53BP1 Enforces Distinct Pre- and Post-resection blocks on homologous recombination. Molecular Cell, 77(1), 26-38.e27.

    Article  CAS  PubMed  Google Scholar 

  • Cao, C., et al. (2020). Discovery of SK-575 as a highly potent and efficacious proteolysis-targeting chimera Degrader of PARP1 for treating cancers. Journal of Medicinal Chemistry, 63(19), 11012–11033.

    Article  CAS  PubMed  Google Scholar 

  • Cao, L., et al. (2009). A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Molecular Cell, 35(4), 534–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ceccaldi, R., et al. (2015). Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature, 518(7538), 258–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Champagne, J., et al. (2020). TAG-RNAi overcomes off-target effects in cancer models. Oncogene, 39(4), 935–945.

    Article  CAS  PubMed  Google Scholar 

  • Chan, D. A., & Giaccia, A. J. (2011). Harnessing synthetic lethal interactions in anticancer drug discovery. Nature Reviews Drug Discovery, 10(5), 351–364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan, E. M., et al. (2019). WRN helicase is a synthetic lethal target in microsatellite unstable cancers. Nature, 568(7753), 551–556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang, H. H. Y., Pannunzio, N. R., Adachi, N., & Lieber, M. R. (2017). Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nature Reviews. Molecular Cell Biology, 18(8), 495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiappa, M., et al. (2022). Combinations of ATR, Chk1 and Wee1 inhibitors with olaparib are active in olaparib resistant Brca1 proficient and deficient murine ovarian cells. Cancers, 14(7), 1807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coleman, R. L., et al. (2017). Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet (london, England), 390(10106), 1949–1961.

    Article  CAS  PubMed  Google Scholar 

  • Colicchia, V., et al. (2017). PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma. Oncogene, 36(33), 4682–4691.

    Article  CAS  PubMed  Google Scholar 

  • Cortes-Ciriano, I., Lee, S., Park, W. Y., Kim, T. M., & Park, P. J. (2017). A molecular portrait of microsatellite instability across multiple cancers. Nature Communications, 8, 15180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Datta, A., et al. (2021a). WRN helicase safeguards deprotected replication forks in BRCA2-mutated cancer cells. Nature Communications, 12(1), 6561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Datta, A., Dhar, S., Awate, S., & Brosh, R. M., Jr. (2021b). Synthetic lethal interactions of RECQ helicases. Trends in Cancer, 7(2), 146–161.

    Article  CAS  PubMed  Google Scholar 

  • Dawicki-McKenna, J. M., et al. (2015). PARP-1 activation requires local unfolding of an autoinhibitory domain. Molecular Cell, 60(5), 755–768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Klein, A., et al. (2000). Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice. Current Biology : CB, 10(8), 479–482.

    Article  PubMed  Google Scholar 

  • De Vos, M., Schreiber, V., & Dantzer, F. (2012). The diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art. Biochemical Pharmacology, 84(2), 137–146.

    Article  PubMed  Google Scholar 

  • Dev, H., et al. (2018). Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nature Cell Biology, 20(8), 954–965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Di Virgilio, M., et al. (2013). Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science (new York, n.y.), 339(6120), 711–715.

    Article  PubMed  Google Scholar 

  • Diab, A., et al. (2019). Multiple Defects Sensitize p53-deficient head and neck cancer cells to the WEE1 kinase inhibition. Molecular Cancer Research : MCR, 17(5), 1115–1128.

    Article  CAS  PubMed  Google Scholar 

  • Dillon, M. T., et al. (2018). PATRIOT: A phase I study to assess the tolerability, safety and biological effects of a specific ataxia telangiectasia and Rad3-related (ATR) inhibitor (AZD6738) as a single agent and in combination with palliative radiation therapy in patients with solid tumours. Clinical and Translational Radiation Oncology, 12, 16–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ditano, J. P., & Eastman, A. (2021). Comparative Activity and Off-Target Effects in Cells of the CHK1 Inhibitors MK-8776, SRA737, and LY2606368. ACS Pharmacology & Translational Science, 4(2), 730–743.

    Article  CAS  Google Scholar 

  • Do, K., et al. (2015). Phase I Study of Single-Agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 33(30), 3409–3415.

    Article  CAS  PubMed  Google Scholar 

  • Do, K. T., et al. (2021). Phase 1 Combination Study of the CHK1 Inhibitor prexasertib and the PARP Inhibitor olaparib in high-grade serous ovarian cancer and other solid tumors. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 27(17), 4710–4716.

    Article  CAS  PubMed  Google Scholar 

  • Dobzhansky, T. (1946). Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics, 31(3), 269–290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dungrawala, H., et al. (2017). RADX Promotes genome stability and modulates chemosensitivity by regulating RAD51 at replication forks. Molecular Cell, 67(3), 374-386.e375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards, S. L., et al. (2008). Resistance to therapy caused by intragenic deletion in BRCA2. Nature, 451(7182), 1111–1115.

    Article  CAS  PubMed  Google Scholar 

  • Eikesdal, H. P., et al. (2021). Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Annals of Oncology : Official Journal of the European Society for Medical Oncology, 32(2), 240–249.

    Article  CAS  PubMed  Google Scholar 

  • Eustermann, S., et al. (2015). Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1. Molecular Cell, 60(5), 742–754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evers, B., et al. (2016). CRISPR knockout screening outperforms shRNA and CRISPRi in identifying essential genes. Nature Biotechnology, 34(6), 631–633.

    Article  CAS  PubMed  Google Scholar 

  • Färkkilä, A., et al. (2020). Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nature Communications, 11(1), 1459.

    Article  PubMed  PubMed Central  Google Scholar 

  • Farmer, H., et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434(7035), 917–921.

    Article  CAS  PubMed  Google Scholar 

  • Fleming, M. S., & Gitler, A. D. (2011). High-throughput yeast plasmid overexpression screen. Journal of Visualized Experiments: Jove. https://doi.org/10.3791/2836

    Article  PubMed  PubMed Central  Google Scholar 

  • Fok, J. H. L., et al. (2019). AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity. Nature Communications, 10(1), 5065.

    Article  PubMed  PubMed Central  Google Scholar 

  • Fong, P. C., et al. (2009). Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. The New England Journal of Medicine, 361(2), 123–134.

    Article  CAS  PubMed  Google Scholar 

  • Garg, A., Shuman, S., & Schwer, B. (2020). A genetic screen for suppressors of hyper-repression of the fission yeast PHO regulon by Pol2 CTD mutation T4A implicates inositol 1-pyrophosphates as agonists of precocious lncRNA transcription termination. Nucleic Acids Research, 48(19), 10739–10752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geenen, J. J. J., & Schellens, J. H. M. (2017). Molecular pathways: targeting the protein kinase wee1 in cancer. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 23(16), 4540–4544.

    Article  CAS  PubMed  Google Scholar 

  • Gell, D., & Jackson, S. P. (1999). Map** of protein-protein interactions within the DNA-dependent protein kinase complex. Nucleic Acids Research, 27(17), 3494–3502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gogola, E., et al. (2018). Selective Loss of PARG Restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell, 33(6), 1078-1093.e1012.

    Article  CAS  PubMed  Google Scholar 

  • Goldberg, F. W., et al. (2020). The Discovery of 7-Methyl-2-[(7-methyl[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one (AZD7648), a Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor. Journal of Medicinal Chemistry, 63(7), 3461–3471.

    Article  CAS  PubMed  Google Scholar 

  • Gómez-Herreros, F., et al. (2017). The ribosome assembly gene network is controlled by the feedback regulation of transcription elongation. Nucleic Acids Research, 45(16), 9302–9318.

    Article  PubMed  PubMed Central  Google Scholar 

  • González-Martín, A., et al. (2019). Niraparib in patients with newly diagnosed advanced ovarian cancer. The New England Journal of Medicine, 381(25), 2391–2402.

    Article  PubMed  Google Scholar 

  • Goodall, J., et al. (2017). Circulating Cell-Free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discovery, 7(9), 1006–1017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goodwin, J. F., & Knudsen, K. E. (2014). Beyond DNA repair: DNA-PK function in cancer. Cancer Discovery, 4(10), 1126–1139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gorecki, L., Andrs, M., Rezacova, M., & Korabecny, J. (2020). Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy. Pharmacology & Therapeutics, 210, 107518.

    Article  CAS  Google Scholar 

  • Guillemette, S., et al. (2015). Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. Genes & Development, 29(5), 489–494.

    Article  CAS  Google Scholar 

  • Guo, E., et al. (2020). FEN1 endonuclease as a therapeutic target for human cancers with defects in homologous recombination. Proceedings of the National Academy of Sciences of the United States of America, 117(32), 19415–19424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ha, G. H., et al. (2019). Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks. Nature Communications, 10(1), 1577.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hahn, W. C., et al. (2021). An expanded universe of cancer targets. Cell, 184(5), 1142–1155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanahan, D. (2022). Hallmarks of cancer: New dimensions. Cancer Discovery, 12(1), 31–46.

    Article  CAS  PubMed  Google Scholar 

  • Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W., & Friend, S. H. (1997). Integrating genetic approaches into the discovery of anticancer drugs. Science New York, n.y., 278(5340), 1064–1068.

    Article  CAS  PubMed  Google Scholar 

  • Henssen, A. G., et al. (2017). Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors. Science Translational Medicine., 9(414), eaam078.

    Article  Google Scholar 

  • Hewitt, G., et al. (2021). Defective ALC1 nucleosome remodeling confers PARPi sensitization and synthetic lethality with HRD. Molecular Cell, 81(4), 767-783.e711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hickson, I. D. (2003). RecQ helicases: Caretakers of the genome. Nature Reviews. Cancer, 3(3), 169–178.

    Article  CAS  PubMed  Google Scholar 

  • Hong, D., et al. (2016). Phase I Study of LY2606368, a checkpoint kinase 1 Inhibitor, in patients with advanced cancer. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 34(15), 1764–1771.

    Article  CAS  PubMed  Google Scholar 

  • Hong, D. S., et al. (2018). Evaluation of Prexasertib, a checkpoint kinase 1 inhibitor, in a phase Ib study of patients with squamous cell carcinoma. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 24(14), 3263–3272.

    Article  CAS  PubMed  Google Scholar 

  • Huang, A., Garraway, L. A., Ashworth, A., & Weber, B. (2020). Synthetic lethality as an engine for cancer drug target discovery. Nature Reviews Drug Discovery, 19(1), 23–38.

    Article  CAS  PubMed  Google Scholar 

  • Huang, P. Q., et al. (2021). Discovery of ZN-c3, a Highly Potent and Selective Wee1 inhibitor undergoing evaluation in clinical trials for the treatment of cancer. Journal of Medicinal Chemistry, 64(17), 13004–13024.

    Article  CAS  PubMed  Google Scholar 

  • Huang, R., & Zhou, P. K. (2021). DNA damage repair: Historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduction and Targeted Therapy, 6(1), 254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hustedt, N., & Durocher, D. (2016). The control of DNA repair by the cell cycle. Nature Cell Biology, 19(1), 1–9.

    Article  PubMed  Google Scholar 

  • Inoue, A., et al. (2021). Sequential Administration of XPO1 and ATR inhibitors enhances therapeutic response in TP53-mutated colorectal cancer. Gastroenterology, 161(1), 196–210.

    Article  CAS  PubMed  Google Scholar 

  • Iorio, F., et al. (2018). Unsupervised correction of gene-independent cell responses to CRISPR-Cas9 targeting. BMC Genomics, 19(1), 604.

    Article  PubMed  PubMed Central  Google Scholar 

  • Javle, M., et al. (2021). Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants: findings from 2 phase 2 nonrandomized clinical trials. JAMA Oncology, 7(5), 693–699.

    Article  PubMed  PubMed Central  Google Scholar 

  • Joshi, P. M., Sutor, S. L., Huntoon, C. J., & Karnitz, L. M. (2014). Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. The Journal of Biological Chemistry, 289(13), 9247–9253.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaelin, W. G., Jr. (2005). The concept of synthetic lethality in the context of anticancer therapy. Nature Reviews. Cancer, 5(9), 689–698.

    Article  CAS  PubMed  Google Scholar 

  • Kategaya, L., Perumal, S. K., Hager, J. H., & Belmont, L. D. (2019). Werner syndrome helicase is required for the survival of cancer cells with microsatellite instability. iScience, 13, 488–497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaufman, B., et al. (2015). Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 33(3), 244–250.

    Article  CAS  PubMed  Google Scholar 

  • Kim, G., et al. (2015). FDA approval summary: Olaparib monotherapy in patients with deleterious germline BRCA-Mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 21(19), 4257–4261.

    Article  CAS  PubMed  Google Scholar 

  • Kim, H., et al. (2020b). Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nature Communications, 11(1), 3726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, R., et al. (2022). Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. Annals of Oncology : Official Journal of the European Society for Medical Oncology, 33(2), 193–203.

    Article  CAS  PubMed  Google Scholar 

  • Kim, S. S., et al. (2020). Histone deacetylase inhibition is synthetically lethal with arginine deprivation in pancreatic cancers with low argininosuccinate synthetase 1 expression. Theranostics, 10(2), 829–840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, S. T., et al. (2021). Phase I Study of Ceralasertib (AZD6738), a Novel DNA damage repair agent, in combination with weekly paclitaxel in refractory cancer. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 27(17), 4700–4709.

    Article  PubMed  Google Scholar 

  • Kondrashova, O., et al. (2017). Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discovery, 7(9), 984–998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kondrashova, O., et al. (2018). Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. Nature Communications, 9(1), 3970.

    Article  PubMed  PubMed Central  Google Scholar 

  • Konstantinopoulos, P. A., et al. (2020). Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: A multicentre, open-label, randomised, phase 2 trial. The Lancet. Oncology, 21(7), 957–968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Konstantinopoulos, P. A., et al. (2021). A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer. Nature Communications, 12(1), 5574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kroll, E. S., Hyland, K. M., Hieter, P., & Li, J. J. (1996). Establishing genetic interactions by a synthetic dosage lethality phenotype. Genetics, 143(1), 95–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kryukov, G. V., et al. (2016). MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science(new York, n.y.), 351(6278), 1214–1218.

    Article  CAS  PubMed  Google Scholar 

  • Kumar, A., et al. (2014). ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell, 158(3), 633–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kunkel, T. A., & Erie, D. A. (2015). Eukaryotic mismatch repair in relation to DNA replication. Annual Review of Genetics, 49, 291–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavin, M. F. (2008). Ataxia-telangiectasia: From a rare disorder to a paradigm for cell signalling and cancer. Nature Reviews. Molecular Cell Biology, 9(10), 759–769.

    Article  CAS  PubMed  Google Scholar 

  • Lee, J. M., et al. (2018). Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: A first-in-class proof-of-concept phase 2 study. The Lancet. Oncology, 19(2), 207–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leijen, S., et al. (2016). Phase I Study Evaluating WEE1 Inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 34(36), 4371–4380.

    Article  CAS  PubMed  Google Scholar 

  • Levesque, A. A., & Eastman, A. (2007). p53-based cancer therapies: Is defective p53 the Achilles heel of the tumor? Carcinogenesis, 28(1), 13–20.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, C. W., et al. (2019). Upregulation of Myt1 promotes acquired resistance of cancer cells to Wee1 inhibition. Cancer Research, 79(23), 5971–5985.

    Article  CAS  PubMed  Google Scholar 

  • Li, A., et al. (2019). Prospects for combining immune checkpoint blockade with PARP inhibition. Journal of Hematology & Oncology, 12(1), 98.

    Article  Google Scholar 

  • Li, F., et al. (2020a). CHK1 Inhibitor Blocks Phosphorylation of FAM122A and promotes replication stress. Molecular Cell, 80(3), 410-422.e416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, F., et al. (2020b). mTOR inhibition overcomes primary and acquired resistance to Wee1 inhibition by augmenting replication stress in epithelial ovarian cancers. American Journal of Cancer Research, 10(3), 908–924.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liang, J., et al. (2020). Genome-Wide CRISPR-Cas9 screen reveals selective vulnerability of ATRX-Mutant Cancers to WEE1 inhibition. Cancer Research, 80(3), 510–523.

    Article  CAS  PubMed  Google Scholar 

  • Liang, S., et al. (2022). Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs. Nature, 601(7894), 643–648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lieb, S., et al. (2019). Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells. eLife, 8, e43333.

    Article  PubMed  PubMed Central  Google Scholar 

  • Litton, J. K., et al. (2018). Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. The New England Journal of Medicine, 379(8), 753–763.

    Article  CAS  PubMed  Google Scholar 

  • Liu, J. F., et al. (2021). Phase II study of the WEE1 inhibitor adavosertib in recurrent uterine serous carcinoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 39(14), 1531–1539.

    Article  CAS  PubMed  Google Scholar 

  • Liu, L., et al. (2018). Synthetic lethality-based identification of targets for anticancer drugs in the human signaling network. Science Reports, 8(1), 8440.

    Article  Google Scholar 

  • Llorens-Agost, M., et al. (2021). POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis. Nature Cell Biology, 23(10), 1095–1104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lord, C. J., & Ashworth, A. (2016). BRCAness revisited. Nature Reviews Cancer, 16(2), 110–120.

    Article  CAS  PubMed  Google Scholar 

  • Lord, C. J., & Ashworth, A. (2017). PARP inhibitors: Synthetic lethality in the clinic. Science (new York, n.y.), 355(6330), 1152–1158.

    Article  CAS  PubMed  Google Scholar 

  • Lowery, C. D., et al. (2019). Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a single agent or chemopotentiator across a range of preclinical pediatric tumor models. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 25(7), 2278–2289.

    Article  CAS  PubMed  Google Scholar 

  • Maiani, E., et al. (2021). AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity. Nature, 592(7856), 799–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mailand, N., et al. (2000). Rapid destruction of human Cdc25A in response to DNA damage. Science (new York, n.y.), 288(5470), 1425–1429.

    Article  CAS  PubMed  Google Scholar 

  • Mateo, J., et al. (2020). Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): A multicentre, open-label, randomised, phase 2 trial. The Lancet Oncology, 21(1), 162–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mateos-Gomez, P. A., et al. (2015). Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature, 518(7538), 254–257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matheson, C. J., Backos, D. S., & Reigan, P. (2016). Targeting WEE1 kinase in cancer. Trends in Pharmacological Sciences, 37(10), 872–881.

    Article  CAS  PubMed  Google Scholar 

  • Matt, S., & Hofmann, T. G. (2016). The DNA damage-induced cell death response: A roadmap to kill cancer cells. Cellular and Molecular Life Sciences: CMLS, 73(15), 2829–2850.

    Article  CAS  PubMed  Google Scholar 

  • McDonald, E. R., 3rd., et al. (2017). Project DRIVE: A compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale Deep RNAi Screening. Cell, 170(3), 577-592.e510.

    Article  CAS  PubMed  Google Scholar 

  • Mengwasser, K. E., et al. (2019). Genetic Screens Reveal FEN1 and APEX2 as BRCA2 synthetic lethal targets. Molecular Cell, 73(5), 885-899.e886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Menolfi, D., et al. (2018). Kinase-dead ATR differs from ATR loss by limiting the dynamic exchange of ATR and RPA. Nature Communications, 9(1), 5351.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mirman, Z., et al. (2018). 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature, 560(7716), 112–116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moiseeva, T. N., Qian, C., Sugitani, N., Osmanbeyoglu, H. U., & Bakkenist, C. J. (2019). WEE1 kinase inhibitor AZD1775 induces CDK1 kinase-dependent origin firing in unperturbed G1- and S-phase cells. Proceedings of the National Academy of Sciences of the United States of America, 116(48), 23891–23893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moore, K. N., et al. (2021). A Phase 1b Trial of Prexasertib in combination with standard-of-care agents in advanced or metastatic cancer. Targeted Oncology, 16(5), 569–589.

    Article  PubMed  Google Scholar 

  • Morgens, D. W., Deans, R. M., Li, A., & Bassik, M. C. (2016). Systematic comparison of CRISPR/Cas9 and RNAi screens for essential genes. Nature Biotechnology, 34(6), 634–636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mortensen, D. S., et al. (2015). Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) kinase inhibitors and the discovery of CC-115. Journal of Medicinal Chemistry, 58(14), 5599–5608.

    Article  CAS  PubMed  Google Scholar 

  • Mullard, A. (2017). Synthetic lethality screens point the way to new cancer drug targets. Nature Reviews Drug Discovery, 16(9), 589–591.

    Article  CAS  PubMed  Google Scholar 

  • Mullenders, J., & Bernards, R. (2009). Loss-of-function genetic screens as a tool to improve the diagnosis and treatment of cancer. Oncogene, 28(50), 4409–4420.

    Article  CAS  PubMed  Google Scholar 

  • Murai, J., et al. (2012). Trap** of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Research, 72(21), 5588–5599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murai, J., et al. (2014). Stereospecific PARP trap** by BMN 673 and comparison with olaparib and rucaparib. Molecular Cancer Therapeutics, 13(2), 433–443.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura, K., et al. (2021). Inhibition of DNA-PK with AZD7648 sensitizes tumor cells to radiotherapy and induces type I IFN-dependent durable tumor control. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 27(15), 4353–4366.

    Article  CAS  PubMed  Google Scholar 

  • Nik-Zainal, S., et al. (2012). Mutational processes molding the genomes of 21 breast cancers. Cell, 149(5), 979–993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niu, T., et al. (2022). Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor. European Journal of Medicinal Chemistry, 228, 114012.

    Article  CAS  PubMed  Google Scholar 

  • Ooi, S. L., et al. (2006). Global synthetic-lethality analysis and yeast functional profiling. Trends in Genetics : TIG, 22(1), 56–63.

    Article  CAS  PubMed  Google Scholar 

  • Pal, S. K., et al. (2021). Effect of Cisplatin and gemcitabine with or without berzosertib in patients with Advanced urothelial carcinoma: a phase 2 randomized clinical trial. JAMA Oncology, 7(10), 1536–1543.

    Article  PubMed  Google Scholar 

  • Parrish, P. C. R., et al. (2021). Discovery of synthetic lethal and tumor suppressor paralog pairs in the human genome. Cell Reports, 36(9), 109597.

    Article  CAS  PubMed  Google Scholar 

  • Pettitt, S. J., et al. (2018). Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nature Communications., 9(1), 1849.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pettitt, S. J., et al. (2020). Clinical BRCA1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discovery, 10(10), 1475–1488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Picco, G., et al. (2021). Werner helicase is a synthetic-lethal vulnerability in mismatch repair-deficient colorectal cancer refractory to targeted therapies, chemotherapy, and immunotherapy. Cancer Discovery, 11(8), 1923–1937.

    Article  CAS  PubMed  Google Scholar 

  • Pilié, P. G., Gay, C. M., Byers, L. A., O’Connor, M. J., & Yap, T. A. (2019). PARP inhibitors: Extending benefit beyond BRCA-Mutant cancers. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 25(13), 3759–3771.

    Article  PubMed  Google Scholar 

  • Plummer, R., et al. (2013). A phase II study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemotherapy and Pharmacology, 71(5), 1191–1199.

    Article  CAS  PubMed  Google Scholar 

  • Poveda, A., et al. (2021). Olaparib tablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Oncology, 22(5), 620–631.

    Article  CAS  PubMed  Google Scholar 

  • Ray Chaudhuri, A., et al. (2016). Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature, 535(7612), 382–387.

    Article  PubMed  Google Scholar 

  • Rodríguez-Galán, O., et al. (2021). A functional connection between translation elongation and protein folding at the ribosome exit tunnel in Saccharomyces cerevisiae. Nucleic Acids Research, 49(1), 206–220.

    Article  PubMed  Google Scholar 

  • Rondinelli, B., et al. (2017). EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nature Cell Biology, 19(11), 1371–1378.

    Article  CAS  PubMed  Google Scholar 

  • Ruiz, S., et al. (2016). A Genome-wide CRISPR Screen Identifies CDC25A as a determinant of sensitivity to ATR inhibitors. Molecular Cell, 62(2), 307–313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakai, W., et al. (2008). Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature, 451(7182), 1116–1120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satoh, M. S., & Lindahl, T. (1992). Role of poly(ADP-ribose) formation in DNA repair. Nature, 356(6367), 356–358.

    Article  CAS  PubMed  Google Scholar 

  • Schaub, J. M., Soniat, M. M., & Finkelstein, I. J. (2022). Polymerase theta-helicase promotes end joining by strip** single-stranded DNA-binding proteins and bridging DNA ends. Nucleic Acids Research, 50(7), 3911–3921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schlacher, K., et al. (2011). Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell, 145(4), 529–542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwer, B., Garg, A., Jacewicz, A., & Shuman, S. (2021). Genetic screen for suppression of transcriptional interference identifies a gain-of-function mutation in Pol2 termination factor Seb1. Proceedings of the National Academy of Sciences of the United States of America, 118(33), e2108105118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sen, T., et al. (2017). Targeting AXL and mTOR pathway overcomes primary and acquired resistance to WEE1 inhibition in small-cell lung cancer. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 23(20), 6239–6253.

    Article  CAS  PubMed  Google Scholar 

  • Sen, T., et al. (2019). Combination Treatment of the Oral CHK1 Inhibitor, SRA737, and low-dose gemcitabine enhances the effect of programmed death ligand 1 blockade by modulating the immune microenvironment in SCLC. Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer, 14(12), 2152–2163.

    Article  CAS  PubMed  Google Scholar 

  • Sheng, H., et al. (2020). ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma. Journal for Immunotherapy of Cancer, 8(1), e000340.

    Article  PubMed  PubMed Central  Google Scholar 

  • Singleton, B. K., Torres-Arzayus, M. I., Rottinghaus, S. T., Taccioli, G. E., & Jeggo, P. A. (1999). The C terminus of Ku80 activates the DNA-dependent protein kinase catalytic subunit. Molecular and Cellular Biology, 19(5), 3267–3277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stracker, T. H., Usui, T., & Petrini, J. H. (2009). Taking the time to make important decisions: The checkpoint effector kinases Chk1 and Chk2 and the DNA damage response. DNA Repair, 8(9), 1047–1054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan-Reed, K., et al. (2018). Simultaneous targeting of PARP1 and RAD52 triggers dual synthetic lethality in BRCA-deficient tumor cells. Cell Reports, 23(11), 3127–3136.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Symington, L. S., & Gautier, J. (2011). Double-strand break end resection and repair pathway choice. Annual Review of Genetics, 45, 247–271.

    Article  CAS  PubMed  Google Scholar 

  • Taglialatela, A., et al. (2017). Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-Family fork remodelers. Molecular Cell, 68(2), 414-430.e418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ter Brugge, P., et al. (2016). Mechanisms of therapy resistance in patient-derived xenograft Models of BRCA1-Deficient breast cancer. Journal of the National Cancer Institute. https://doi.org/10.1093/jnci/djw148

    Article  PubMed  Google Scholar 

  • Thomas, A., et al. (2018). Phase I Study of ATR Inhibitor M6620 in combination with topotecan in patients with advanced solid tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 36(16), 1594–1602.

    Article  CAS  PubMed  Google Scholar 

  • Thomas, A., et al. (2021). Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress. Cancer Cell, 39(4), 566-579.e567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tomimatsu, N., et al. (2014). Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nature Communications, 5, 3561.

    Article  PubMed  Google Scholar 

  • Tsherniak, A., et al. (2017). Defining a cancer dependency map. Cell, 170(3), 564-576.e516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Turner, N. C., et al. (2008). A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. The EMBO Journal, 27(9), 1368–1377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tutt, A. N. J., et al. (2021). Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. The New England Journal of Medicine, 384(25), 2394–2405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Bussel, M. T. J., et al. (2021). A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. British Journal of Cancer, 124(4), 728–735.

    Article  PubMed  Google Scholar 

  • Wang, C., et al. (2021). Genetic vulnerabilities upon inhibition of DNA damage response. Nucleic Acids Research, 49(14), 8214–8231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, J., et al. (2016). Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK. Nature Communications, 7, 11363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, J., et al. (2019). FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma. Oncogene, 38(41), 6737–6751.

    Article  CAS  PubMed  Google Scholar 

  • Wang, T., et al. (2015). Identification and characterization of essential genes in the human genome. Science (new York, n.y.), 350(6264), 1096–1101.

    Article  CAS  PubMed  Google Scholar 

  • Wang, W., et al. (2019). Combined gene essentiality scoring improves the prediction of cancer dependency maps. eBioMedicine, 50, 67–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wheeler, D. A., et al. (2021). Molecular features of cancers exhibiting exceptional responses to treatment. Cancer Cell, 39(1), 38-53.e37.

    Article  CAS  PubMed  Google Scholar 

  • Wilson, Z., et al. (2022). ATR Inhibitor AZD6738 (Ceralasertib) exerts antitumor activity as a monotherapy and in combination with chemotherapy and the PARP inhibitor olaparib. Cancer Research, 82(6), 1140–1152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wyatt, D. W., et al. (2016). Essential Roles for Polymerase θ-mediated end joining in the repair of chromosome breaks. Molecular Cell, 63(4), 662–673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu, G., et al. (2015). REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature, 521(7553), 541–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, E. S., et al. (2021). A Phase 1b trial of prexasertib in combination with chemoradiation in patients with locally advanced head and neck squamous cell carcinoma. Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology, 157, 203–209.

    Article  CAS  PubMed  Google Scholar 

  • Yap, T. A., et al. (2020). Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as monotherapy or in combination with carboplatin in patients with advanced solid tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 38(27), 3195–3204.

    Article  CAS  PubMed  Google Scholar 

  • Yap, T. A., et al. (2021). Ceralasertib (AZD6738), an Oral ATR kinase inhibitor, in combination with carboplatin in patients with advanced solid tumors: A Phase I Study. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research, 27(19), 5213–5224.

    Article  CAS  PubMed  Google Scholar 

  • Yazinski, S. A., et al. (2017). ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes & Development, 31(3), 318–332.

    Article  CAS  Google Scholar 

  • Zatreanu, D., et al. (2021). Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nature Communications, 12(1), 3636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, Z., et al. (2020). Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1). Journal of Enzyme Inhibition and Medicinal Chemistry, 35(1), 1606–1615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao, Q., Lan, T., Su, S., & Rao, Y. (2019). Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule. Chemical Communications (cambridge, England), 55(3), 369–372.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, J., et al. (2021). A first-in-class Polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nature Cancer, 2(6), 598–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences to M.D (2021-RC310-013), Bei**g Hope Run Special Fund of Cancer Foundation of China to M.D (LC2021R02) and the CAMS Innovation Fund for Medical Sciences to M.D (2021-I2M-1-067).

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei**g, 100021, China

    **n Xu

  2. Department of Dermatology, University of California San Diego, San Diego, CA, USA

    Somaira Nowsheen

  3. State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei**g, 100021, China

    Min Deng

Authors
  1. **n Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Somaira Nowsheen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XX: data curation, writing—original draft. SN: writing—review and editing. MD: conceptualization, funding acquisition, resources, supervision, writing—review and editing.

Corresponding author

Correspondence to Min Deng.

Ethics declarations

Conflict of interests

The authors declare that they have no competing financial interests.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, X., Nowsheen, S. & Deng, M. Exploring the DNA damage response pathway for synthetic lethality. GENOME INSTAB. DIS. 4, 98–120 (2023). https://doi.org/10.1007/s42764-022-00087-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42764-022-00087-w

Keywords

Search

Navigation