The Effects of Deregulated DNA Damage Signalling on Cancer Chemotherapy Response and Resistance

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2012 Aug 25

PMID 22918414

Citations 308

Authors

Peter Bouwman

Jos Jonkers

Affiliations

Soon will be listed here.

Abstract

Tumours with specific DNA repair defects can be completely dependent on back-up DNA repair pathways for their survival. This dependence can be exploited therapeutically to induce synthetic lethality in tumour cells. For instance, homologous recombination (HR)-deficient tumours can be effectively targeted by DNA double-strand break-inducing agents. However, not all HR-defective tumours respond equally well to this type of therapy. Tumour cells may acquire resistance by invoking biochemical mechanisms that reduce drug action or by acquiring additional alterations in DNA damage response pathways. A thorough understanding of these processes is important for predicting treatment response and for the development of novel treatment strategies that prevent the emergence of therapy-resistant tumours.

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References

Mostoslavsky R, Chua K, Lombard D, Pang W, Fischer M, Gellon L . Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006; 124(2):315-29. DOI: 10.1016/j.cell.2005.11.044. View

Bao S, Wu Q, McLendon R, Hao Y, Shi Q, Hjelmeland A . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-60. DOI: 10.1038/nature05236. View

Adhikari S, Choudhury S, Mitra P, Dubash J, Sajankila S, Roy R . Targeting base excision repair for chemosensitization. Anticancer Agents Med Chem. 2008; 8(4):351-7. DOI: 10.2174/187152008784220366. View

Xie A, Hartlerode A, Stucki M, Odate S, Puget N, Kwok A . Distinct roles of chromatin-associated proteins MDC1 and 53BP1 in mammalian double-strand break repair. Mol Cell. 2007; 28(6):1045-57. PMC: 2275782. DOI: 10.1016/j.molcel.2007.12.005. View

Drost M, Zonneveld J, van Dijk L, Morreau H, Tops C, Vasen H . A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. Hum Mutat. 2009; 31(3):247-53. DOI: 10.1002/humu.21180. View

Feldser D, Kostova K, Winslow M, Taylor S, Cashman C, Whittaker C . Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010; 468(7323):572-5. PMC: 3003305. DOI: 10.1038/nature09535. View

Baylin S, Jones P . A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011; 11(10):726-34. PMC: 3307543. DOI: 10.1038/nrc3130. View

ElShamy W, Livingston D . Identification of BRCA1-IRIS, a BRCA1 locus product. Nat Cell Biol. 2004; 6(10):954-67. DOI: 10.1038/ncb1171. View

Zhou W, Gurubhagavatula S, Liu G, Park S, Neuberg D, Wain J . Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clin Cancer Res. 2004; 10(15):4939-43. DOI: 10.1158/1078-0432.CCR-04-0247. View

10.

Christophorou M, Ringshausen I, Finch A, Swigart L, Evan G . The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature. 2006; 443(7108):214-7. DOI: 10.1038/nature05077. View

11.

Fernandez-Capetillo O, Chen H, Celeste A, Ward I, Romanienko P, Morales J . DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol. 2002; 4(12):993-7. DOI: 10.1038/ncb884. View

12.

Issaeva N, Thomas H, Djureinovic T, Djurenovic T, Jaspers J, Stoimenov I . 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res. 2010; 70(15):6268-76. PMC: 2913123. DOI: 10.1158/0008-5472.CAN-09-3416. View

13.

Borst P, Wessels L . Do predictive signatures really predict response to cancer chemotherapy?. Cell Cycle. 2010; 9(24):4836-40. DOI: 10.4161/cc.9.24.14326. View

14.

Ben david Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck B, Beller U . Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol. 2002; 20(2):463-6. DOI: 10.1200/JCO.2002.20.2.463. View

15.

Doles J, Oliver T, Cameron E, Hsu G, Jacks T, Walker G . Suppression of Rev3, the catalytic subunit of Pol{zeta}, sensitizes drug-resistant lung tumors to chemotherapy. Proc Natl Acad Sci U S A. 2010; 107(48):20786-91. PMC: 2996428. DOI: 10.1073/pnas.1011409107. View

16.

Norquist B, Wurz K, Pennil C, Garcia R, Gross J, Sakai W . Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011; 29(22):3008-15. PMC: 3157963. DOI: 10.1200/JCO.2010.34.2980. View

17.

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

18.

Bykov V, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P . Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med. 2002; 8(3):282-8. DOI: 10.1038/nm0302-282. View

19.

Waisfisz Q, Morgan N, Savino M, de Winter J, van Berkel C, Hoatlin M . Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nat Genet. 1999; 22(4):379-83. DOI: 10.1038/11956. View

20.

Postel-Vinay S, Vanhecke E, Olaussen K, Lord C, Ashworth A, Soria J . The potential of exploiting DNA-repair defects for optimizing lung cancer treatment. Nat Rev Clin Oncol. 2012; 9(3):144-55. DOI: 10.1038/nrclinonc.2012.3. View