title: Therapeutic opportunities within the DNA damage response.
abstract: The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets.
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.affiliation: 1] Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. [2] Bluefool Innovations, 4 May Close, Sandhurst, Berkshire GU47 0UG, UK.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Schierz
authors.affiliation: Translational Drug Discovery Group, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Ward
authors.affiliation: Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Bissan
authors.initials: B
authors.lastname: Al-Lazikani
authors.affiliation: 1] Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. [2] Translational Drug Discovery Group, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QJ, UK.
authors.forename: Frances M G
authors.initials: FM
authors.lastname: Pearl
mesh_terms: D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics