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Predictive Biomarkers for Cancer Therapy with PARP Inhibitors

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Predictive Biomarkers for Cancer Therapy with PARP Inhibitors Oncogene (2014) 33, 3894–3907 & 2014 Macmillan Publishers Limited All rights reserved 0950-9232/14 www.nature.com/onc REVIEW Predictive biomarkers for cancer therapy with PARP inhibitors J Michels1,2,3, I Vitale4,5, M Saparbaev2,3,6, M Castedo1,2,3,11 and G Kroemer1,2,3,7,8,9,10,11 Poly(ADP-ribose) polymerase (PARP) inhibitors have raised high expectations for the treatment of multiple malignancies. PARP inhibitors, which can be used as monotherapies or in combination with DNA-damaging agents, are particularly efficient against tumors with defects in DNA repair mechanisms, in particular the homologous recombination pathway, for instance due to BRCA mutations. Thus, deficient DNA repair provides a framework for the success of PARP inhibitors in medical oncology. Here, we review encouraging results obtained in recent clinical trials investigating the safety and efficacy of PARP inhibitors as anti- cancer agents. We discuss emerging mechanisms of regulation of homologous recombination and how inhibition of DNA repair might be used in cancer therapy. We surmise that the identification of patients that are likely to benefit from PARP inhibition will improve the clinical use of PARP inhibitors in a defined target population. Thus, we will place special emphasis on biomarker discovery. Oncogene (2014) 33, 3894–3907; doi:10.1038/onc.2013.352; published online 16 September 2013 Keywords: PAR; base excision repair; homologous recombination; BRCAness; synthetic lethality INTRODUCTION PARP1 IN PHYSIOLOGICAL AND PATHOLOGICAL RESPONSES The superfamily of poly(ADP-ribose) (PAR) polymerases (PARPs),1 PARP1 is historically known as a sensor of DNA nicks, contributing whose discovery dates back to the early 1960s, nowadays en- to the single-strand break repair, the orchestration of the DNA compasses 17 distinct members that participate in a wide array damage response (DDR) and the maintenance of genomic of cell functions, including DNA transcription, DNA repair, stability.10,11 Nevertheless, several recent studies have led to the genomic stability maintenance, cell cycle regulation as well as identification of a plethora of novel roles for PARP1, placing its non-apoptotic cell death (Table 1).2–5 activity at the center of the cellular stress response network. PARP1, a multifunctional enzyme of 113 kDa, is the most PARP1 À / À knockout mice exhibit (i) increased genetic instability abundant, ubiquitously expressed and best-characterized member as measured by the frequency of micronuclei, sister chromatid of the superfamily.6 PARP1 has a highly conserved structural and exchanges and other chromosome aberrations as well as (ii) major functional organization including: an N-terminal double zinc finger DNA repair defects coupled to hypersensitivity to alkylating agents 12 DNA-binding domain, a central auto-regulation domain and a and g-radiation. Nonetheless, the inhibition of PARP is not lethal 13 À / À C-terminal catalytic domain that binds oxidized nicotinamide for mammals, and Parp1 mice are viable and fertile, even adenine dinucleotide (NAD þ ).7 PARP1 is a DNA nick sensor that though they manifest accelerated aging and exhibit a higher þ incidence of spontaneous or carcinogen-induced tumors than utilizes NAD as a substrate to catalyze the covalent attachment 14 of ADP-ribose units to the g-carboxyl group of Glu residues of a wild-type controls. However, the simultaneous loss of PARP1 and PARP2 is lethal at the onset of gastrulation, suggesting that the two wide array of target proteins. This post-translational modification 15 known as poly-ADP-ribosylation or PARylation increases more PARP proteins have redundant roles in embryogenesis. than 500-fold in the presence of DNA-strand breaks.8 Although PARP1 accounts for the vast majority (B85%) of PAR polymer PARP1 and the DDR synthesis, five other members have catalytic activity of PARylation, Due to the continuous exposure to endogenous and exogenous namely PARP2, PARP3, PARP4 and PARP5A/B (also known as DNA-damaging insults, cells experience DNA lesions such as SSBs 9 tankyrase1/2). Recently, Hottiger reported a new classification for and double-strand breaks (DSBs) that require continuous activa- the ADP-ribosyl transferases grouping the PARP family members tion of DNA repair pathways (Box 1). and distinguishing proteins with mono or poly(ADP)ribosylation The levels of PARP1 protein increase in response to DNA activity.9 damage,16 and PARP1 contributes to both SSB and DSB repair. Here, we provide an overview on the roles of PARP1, focusing PARP1 associates with persisting SSBs or DSBs where it becomes on its involvement in cellular stress management, and the activated and catalyzes the PARylation of multiple nuclear acceptor possibility to target PARP1 for the treatment of cancer. We will proteins adjacent to the DNA break including that of PARP1 itself, devote special attention to the discovery of predictive biomarkers histones, DNA repair proteins, chromatin regulators and transcription that may improve patient selection. factors.7,17 PARylation facilitates the chromatin decondensation, 1INSERM, U848, Villejuif, France; 2Institut Gustave Roussy, Villejuif, France; 3Universite´ de Paris Sud, Villejuif, France; 4Regina Elena National Cancer Institute, Roma, Italy; 5National Institute of Health, Rome, Italy; 6CNRS UMR8200, Villejuif, France; 7Metabolomics Platform, Institut Gustave Roussy, Villejuif, France; 8Centre de Recherche des Cordeliers, Paris, France; 9Poˆle de Biologie, Hoˆpital Europe´en Georges Pompidou, AP-HP, Paris, France and 10Faculty of Medicine, Universite´ Paris Descartes, Paris, France. Correspondence: Dr M Castedo or Professor G Kroemer, INSERM U848, Institut Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France. E-mail: [email protected] or [email protected] 11These authors share senior co-authorship. Received 17 June 2013; revised 9 July 2013; accepted 12 July 2013; published online 16 September 2013 Anticancer profile of PARP inhibitors J Michels et al 3895 Table 1. Multiple PARP functions Box 1 DNA repair pathways Actor Function Reference Base excision repair (BER) is a DNA repair pathway that DNA repair XRCC1 BER 11,22 removes non-bulky base lesions in form of the free bases, as DDB2, XPA NER 24–26 they occur after spontaneous, oxidative and alkylating DNA MRE11 HRR 27 damage.181 BER includes different effectors acting at distinct 35 DNA-PKC NHEJ steps. In human cells DNA glycosylases (for example, 88 8-oxoguanine-DNA glycosylase (OGG1), alkyl-N-purine-DNA Genomic Topoisomerase I Genomic glycosylase (ANPG), endonuclease III DNA glycosylase hNTH1) stability maintenance 182–185 Telomere Genomic stability 199 retrieve the damaged bases generating abasic sites that then are cleaved by AP endonuclease 1, APE1, inducing single- endings 186 Mitotic spindle Mitosis 199 strand breaks (SSBs). PARP1 and PARP2 attract different poles repair enzymes to the DNA lesion site (for example, X-ray cross-complementing factor 1 XRCC1, polymerase b,pro- DNA Histone H1 Decondensation of 200 liferating cell nuclear antigen (PCNA), ligase 3).37 transcription the double DNA Nucleotide excision repair (NER) is a pluripotent pathway helix 201 for recognition and removal of bulky helix disturbing DNA Cell cycle c-Fos, c-Myc G0-G1 transition lesions generated by UV irradiation and anticancer agents progression Inflammation TNF-a, NF-kB, Acute and chronic 62 such as cisplatin (CDDP). NER involves dual incisions that HMGB1 inflammation bracket lesion site and release of the 24–32 nucleotide-long Cell NAD þ Mitochondrial 66 oligomer containing damaged residues. Two sub-pathways metabolism respiration are identified, (i) the transcription-coupled repair (TC-NER) in transcriptionally active genes and (ii) the global genomic Cell death/ AIF Parthanatos 47 repair (GG-NER) operating on the entire genome.187 RNA survival polymerase II is stalled at the DNA lesions are sensed by ROS Apoptosis 202 66,202 cockayne syndrome WD repeat proteins (CSA and CSB) in TC- Glycolysis Necrosis NER and by Xeroderma pigmentosum (XPC) in GG-NER.188 In inhibition, NAD þ depletion both pathways, the lesions are excised by endonucleases (for AMPK activation Autophagy 52 example, XPG and ERCC1-XPF) and resulting DNA gap is then filled and sealed by DNA polymerases d, e and ligase III, respectively. NER also contributes to repair intra and Abbreviations: AIF, apoptosis-inducing factor; AMPK, AMP kinase; ATM, interstrand crosslinks (ICL) and oxidative DNA damage. ataxia-telangiectasia mutated; BER, base excision repair; DDB2, damaged Mismatch repair (MMR) is a system that recognizes and DNA-binding protein; DNA-PKc, DNA-dependant protein kinase; HRR, homologous recombinational repair; NAD þ, nicotinamide adenine dinu- repairs DNA replication and recombination errors, such as cleotide; NER, nucleotide excision repair; NHEJ, non-homologous end mismatched bases, deletions and insertions. In human cells joining; PARP, poly-(ADP-ribose) polymerase; ROS, reactive oxygen species; two major heterodimers: Msh2/Msh6 (MutSa), and Msh2/ TNF-a, tumor necrosis factor a; XPA, xeroderma pigmentosum comple- Msh3 (MutSb) recognize DNA mismatches and trigger their mentary group A; XRCC1, X-ray repair cross-complementing 1. removal by recruiting MutLa (MLH1/PMS2) and MutLb (MLH1/PMS1) complexes. Direct repair (DR) is the direct reversal of a damaged base to its native state without excision and de novo DNA synthesis. thereby rendering DNA lesions accessible to the repair machinery. In At present, there are three types of DNA damage known to addition,
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