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Originally published as JCO Early Release 10.1200/JCO.2008.16.0812 on June 30 2008 © 2008 American Society of Clinical Oncology.
A Synthetic Lethal Therapeutic Approach: Poly(ADP) Ribose Polymerase Inhibitors for the Treatment of Cancers Deficient in DNA Double-Strand Break Repair
From the Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom Corresponding author: Alan Ashworth, MD, the Institute of Cancer Research, 237 Fulham Rd, London, SW3 6JB, United Kingdom; e-mail: alan.ashworth{at}icr.ac.uk
Cancer cells frequently harbor defects in DNA repair pathways, leading to genomic instability. This can foster tumorigenesis but also provides a weakness in the tumor that can be exploited therapeutically. Tumors with compromised ability to repair double-strand DNA breaks by homologous recombination, including those with defects in BRCA1 and BRCA2, are highly sensitive to blockade of the repair of DNA single-strand breaks via the inhibition of the enzyme poly(ADP) ribose polymerase. This provides the basis for a novel synthetic lethal approach to cancer therapy.
DNA is continually damaged by environmental exposures and endogenous activities, such as DNA replication and cellular free radical generation, which cause diverse lesions including base modifications, double-strand breaks (DSBs), single-strand breaks (SSBs), and intrastrand and interstrand cross-links.1 These aberrations are repaired by distinct DNA repair pathways, which are coordinated to maintain the stability and integrity of the genome. This faithful repair of DNA damage is an essential prerequisite for the maintenance of genomic integrity and cellular and organismal viability. Where one DNA strand is affected and the intact complementary strand is available as a template, the base-excision repair (BER), nucleotide-excision repair, or mismatch repair pathways are used. Among DNA breaks, DSBs are more problematic to repair than SSBs, as the complementary strand is not available as a template. Two main DSB repair pathways are available within eukaryotic cells: nonhomologous end-joining (NHEJ) and homologous recombination (HR). HR can be further subdivided into the gene conversion (GC) and single-strand annealing (SSA) subpathways.1 Both GC and SSA rely on sequence homology for repair, whereas NHEJ uses no or little homology.2,3 NHEJ is the most important pathway for the repair of DSBs during G0, G1 and early S phases of the cell cycle, although it is likely active throughout the cell cycle.4,5 This form of DSB repair usually results in changes in DNA sequence at the break site and, occasionally, in the joining of previously unlinked DNA molecules, potentially resulting in gross chromosomal rearrangements, such as translocations. GC uses a homologous sequence, preferably the sister chromatid, as a template to resynthesize the DNA surrounding the DSB and therefore generally results in accurate repair of the break. Repair by GC is critically dependent on the recombinase function of RAD51 and is facilitated by a number of other proteins. SSA also involves the use of homologous sequences for the repair of DSBs, but unlike GC, SSA is RAD51-independent and involves the annealing of DNA strands formed after resection at the DSB. The detailed mechanism of SSA is still obscure but it frequently results in the loss of one of the homologous sequences and deletion of the intervening sequence.6 SSA is a potentially important pathway of mutagenesis, as a significant fraction of mammalian genomes consist of repetitive elements. GC and SSA are cell cycle regulated and are most active in S-G2 phases of the cell cycle.7
Heterozygous germline mutations in the BRCA1 and BRCA2 genes confer a high risk of breast (up to 85% lifetime risk) and ovarian cancer (10% to 40%) in addition to a significantly increased risk of pancreatic, prostate, and male breast cancer.8 The genes have been classified as tumor suppressors, as the wild-type BRCA allele is lost in tumors, which occurs by a variety of mechanisms. The BRCA1 and BRCA2 genes encode large proteins that likely function in multiple cellular pathways, including transcription, cell cycle regulation, and the maintenance of genome integrity. However, it is the roles of BRCA1 and BRCA2 in DNA repair that have been best documented.9 BRCA1 associates and colocalizes with RAD5110 and the BRCA1-binding protein BARD1.11 Furthermore, BRCA1-deficient cells are highly sensitive to ionizing radiation and display chromosomal instability, which is likely to be a direct consequence of unrepaired DNA damage.12,13 The similar genomic instability in BRCA1- and BRCA2-deficient cells and the interaction of both BRCA1 and BRCA2 with RAD51 suggests a functional link between the three proteins in the RAD51-mediated DNA damage repair process. However, whereas BRCA2 is directly involved in RAD51-mediated repair, affecting the choice between GC and SSA (see below), BRCA1 acts upstream of these pathways9; both GC and SSA are reduced in BRCA1-deficient cells, placing BRCA1 before the branch point of GC and SSA6 (Fig 1).
Cells deficient in BRCA1 or BRCA2 function show a high degree of chromosome instability, including chromosome breaks and radial chromosomes14-16 (Fig 2). These aberrations accumulate spontaneously but are exacerbated by DNA damaging agents that induce DSBs, in particular, DNA cross-linking agents. BRCA1 has a role in signaling DNA damage and cell cycle checkpoint regulation,9 whereas BRCA2 has a more direct role in DNA repair itself. BRCA2 is thought to promote genomic stability through a role in the error-free repair of DSBs by GC via association with RAD51. Aberrations arising in BRCA2-deficient cells arise at least in part by the use of the SSA pathway. NHEJ, however, is apparently unaffected in BRCA2-deficient cells.14,18 Loss of BRCA2, therefore, results in the repair of DSBs by preferential use of error-prone mechanism potentially explaining the apparent chromosome instability associated with BRCA2 deficiency.15
The physical interaction between BRCA2 and RAD51 is essential for error-free DSB repair. BRCA2 is required for the localization of RAD51 to sites of DNA damage, where RAD51 forms the nucleoprotein filament required for recombination. Foci of RAD51 protein are apparent in the nucleus after certain forms of DNA damage, and these likely represent sites of repair by HR; BRCA2-deficient cells do not form RAD51 foci in response to DNA damage.19 Two different domains within BRCA2 interact with RAD51, the eight BRC repeats in the central part of the protein and a distinct domain, TR2, at the C terminus. Recently, it has been proposed that BRC repeats hold RAD51 in an essentially inactive monomeric form, and when damage occurs, the BRCA2-RAD51 complex localizes to the site of DNA damage.20-22 Then a critical serine in the C terminus of BRCA2 becomes phosphorylated, activating TR2, which can then support RAD51 oligomerization and nucleoprotein filament formation. This filament can then invade and pair with a homologous DNA duplex, initiating strand exchange between the paired DNA molecules. The BRCA2 DNA binding domain (DBD) also stimulates homologous pairing and the strand-exchange activities of RAD51, suggesting that BRCA2 might facilitate RAD51-mediated recombination by binding to the dsDNA-ssDNA junction of the resected DSB.23
Endogenous base damage, including SSBs, is the most common DNA aberration, and it has been estimated that the average cell may repair 10,000 such lesions every day. BER is an important pathway for the repair of SSBs and involves the sensing of the lesion followed by the recruitment of a number of other proteins. Poly(ADP) ribose polymerase (PARP-1) is a critical component of the major short-patch BER pathway. PARP is an enzyme discovered more than 40 years ago24 that produces large branched chains of poly(ADP) ribose (PAR) from NAD+. In humans, there are 17 members of the PARP gene family, but most of these are poorly characterized.25,26 The abundant nuclear protein PARP-1 senses and binds to DNA nicks and breaks, and these result in activation of catalytic activity, causing poly(ADP)ribosylation of PARP-1 itself, as well as other acceptor proteins, such as histones. This modification potentially signals the recruitment of other components of DNA repair pathways, as well as modifying the activity of proteins.25,26 The highly negatively charged PAR that is produced around the site of damage may also serve as an antirecombinogenic factor. Outside of the BER pathway, PARP enzymes have been implicated in numerous cellular pathways.25,26
Synthetic lethality is defined as the situation when mutation in either of two genes individually has no effect but combining the mutations leads to death27 (Fig 3). This effect was first described and studied in genetically tractable organisms such as Drosophila and yeast.27,28 This effect can arise because of a number of different gene-gene interactions. Examples include two genes in separate semi-redundant or co-operating pathways and two genes acting in the same pathway where loss of both critically affects flux through the pathway. The implication is that targeting one of these genes in a cancer where the other is defective should be selectively lethal to the tumor cells but not toxic to the normal cells. In principle, this should lead to a large therapeutic window.28 The original suggestion that the concept of synthetic lethality could be used in the selection or development of cancer therapeutics came from Hartwell et al29 and came from experiments performed in yeast. Comprehensive synthetic lethal screens have now been performed in a number of model organisms (eg, Ooi et al30) and, to a certain extent, in human cells.31 These have revealed multiple potential gene-gene interactions that could be exploited clinically. Nevertheless, therapies designed based on synthetic lethal interactions have not been so far clinically implemented.28
PARP-1 inhibition causes failure of the repair of SSB lesions but does not affect DSB repair.32 However, a persistent DNA SSB encountered by a DNA replication fork will cause stalling of the fork and may result in either fork collapse or the formation of a DSB.33 Therefore, loss of PARP-1 increases the formation of DNA lesions that might be repaired by GC. As loss of function of either BRCA1 or BRCA2 impairs GC,15,34,35 loss of PARP-1 function in a BRCA1 or BRCA2 defective background could result in the generation of replication-associated DNA lesions normally repaired by sister chromatid exchange. If so, this might lead to cell cycle arrest and/or cell death. Therefore, PARP inhibitors could be selectively lethal to cells lacking functional BRCA1 or BRCA2 associated with minimal toxicity to normal cells. This would indicate a synthetic lethal interaction between PARP and BRCA1 or BRCA2. Exemplifying this principle, decreasing PARP-1 expression levels using RNA interference causes a reduction in the clonogenic survival of BRCA1- and BRCA2-deficient cells compared with wild-type cells.36 This suggested that chemical inhibitors of PARP activity might have similar effects. Potent inhibitors of PARP were used to probe test the sensitivity of cells deficient in either BRCA1 or BRCA2. Cell survival assays showed that cell lines lacking wild-type BRCA1 or BRCA2 were extremely sensitive to the potent PARP inhibitors KU0058684 and KU0058948 compared with heterozygous mutant or wild-type cells36 (Fig 4). Similar results were obtained with nonembryonic cells such as Chinese hamster ovary cells deficient in Brca2,10 which showed a greater than 1,000-fold enhanced sensitivity compared with a Brca2-complemented derivative.36 Depletion of BRCA1 mRNA in MCF7 human breast cancer cells or of BRCA2 mRNA in MCF7 or MDA-MB-231 cells also induced hypersensitivity to PARP inhibition.36,38 No selective effect on cells heterozygous for BRCA1 or BRCA2 mutations was apparent; this is important because the normal tissue in BRCA patients carries only one copy of the relevant wild-type BRCA gene. Potent PARP inhibitors seem to be required, as relatively ineffective PARP inhibitors do not cause this effect.39,40
To explain these observations, a model was proposed whereby persistent single-strand gaps in DNA caused by PARP inhibition,41 when encountered by a replication fork, might trigger fork arrest, collapse, and/or a DSB.33,42 Normally, these DSBs would be repaired by RAD51-dependent GC.43 However, in the absence of BRCA1 or BRCA2, the replication fork cannot be restarted and collapses,44 causing persistent chromatid breaks. When repaired by the alternative error-prone DSB repair mechanisms of SSA or NHEJ, large numbers of chromatid aberrations would be induced, leading to cell lethality. That it is the defect in GC that is being targeted in BRCA-deficient cells is supported by the demonstration that deficiency in other genes implicated in HR also confers sensitivity to PARP inhibitors.45 This further suggests that this approach may be more widely applicable in the treatment of sporadic cancers with impairments of the HR pathway or BRCAness (Turner et al46 and see Use of PARP Inhibitors in Sporadic Cancers).
Clinical Development The profound sensitivity of BRCA mutant cells to PARP inhibition has led to the development of a number of clinical trials to test the efficiency of this approach. The potent PARP inhibitor KU-0059436/AZD2281 (AstraZeneca, Macclesfield, United Kingdom) is currently being tested in a number of trials. In a phase I trial, preliminary observations in patients carrying BRCA mutations with ovarian cancer suggest low toxicities, with some promising indicators of responses measured radiologically and using tumor markers.49 Phase II trials of KU-0059436/AZD2281 for breast and ovarian cancers in BRCA carriers are now also underway.50 Other PARP inhibitors are also being assessed clinically for this indication. The first phase I trial of a PARP inhibitor (AG0146999; Pfizer, New York, NY) in cancer was in combination with temozolomide, and this drug is now undergoing assessment as a single agent in BRCA carriers with cancer.51 A number of other PARP inhibitors are in clinical development.52
Potential Mechanisms of Resistance PARP inhibitor–resistant (PIR) clones developed by exposure to the potent PARP inhibitor KU005894836,37 are highly resistant (more than 1,000-fold) to the drug.17 PIR clones are also cross-resistant to the DNA cross-linking agent cisplatin but not to the microtubule-stabilizing drug docetaxel. KU0058948 and cisplatin both exert their effects on BRCA-deficient cells by increasing the frequency of misrepaired DSBs in the absence of effective HR. Therefore, this suggests that the resistance of PIR clones to KU0058948 might be because of restored HR. This contention was supported by the acquisition in PIR cells of the ability to form RAD51 foci after KU0058948 treatment or exposure to ionizing radiation. The ability of mitomycin to cause genomic instability is indicative of defective HR, and mitomycin-induced chromosomal aberrations were frequent in CAPAN1 cells but significantly reduced in PIR cells.17 cDNA and genomic DNA sequencing from PIR clones revealed the presence of novel BRCA2 alleles with deletions of up to 58 kb; some of these resulted in elimination of the c.6174delT mutation and restoration of an open reading frame, including five BRC repeats, the C-terminal nuclear localization sequences, and the TR2 RAD51 interaction domain. Other novel BRCA2 species lacked three BRC repeats (BRC 6, 7, and 8) and either all or most of the proposed DBD. Examination of the nucleotide sequences surrounding the BRCA2 deletions revealed, in almost all cases, short regions of sequence identity associated with the ends of the deleted region. These are indicative of defective DNA repair pathway utilized in BRCA defective cells. It seems possible, therefore, that these deletions arose because of the BRCA2 mutation and consequential DNA repair dysfunction in the parental CAPAN1 cells.17 It is not yet possible to assess mechanisms of resistance to PARP inhibitors in patient material because clinical trials are at an early stage. However, cisplatin and carboplatin are frequently used for the treatment of ovarian cancer, including some individuals with BRCA1 or BRCA2 mutations. As mentioned above, platinum salts are thought to exert their BRCA-selective effects by a similar mechanism to PARP inhibitors.48 Clinical observations suggest that BRCA1 or BRCA2 mutation carriers with ovarian cancer tend to respond better to these agents compared with patients with no family history of the disease55,56; however, resistance does eventually occur. Therefore, the BRCA2 gene was sequenced in tumor material from patients bearing the BRCA2 c.6174delT mutation whose ovarian carcinomas were resistant to carboplatin treatment. This revealed deletions in the BRCA2 gene, which restored the open reading frame.17,57 These observations suggest that a specific mutation (c.6174delT) in BRCA2 and sensitivity to therapeutics in cell lines and patients can be suppressed by intragenic deletion. However, it is not yet clear whether other mutations in BRCA2 or BRCA1 can be reverted in this way and cause resistance to PARP inhibitors. Nevertheless, this may indicate that the most appropriate use of these agents is earlier in the disease process, where the disease burden is smaller, to reduce the probability of resistance based on stochastic genetic reversion.
Although germline mutations in BRCA1 or BRCA2 contribute to a substantial proportion of hereditary breast and ovarian cancer, inactivation of these genes by mutation occurs only infrequently in sporadic cancers.46 Nevertheless, increasing data indicate that these genes, or other components of the same biochemical pathways in which BRCA1 or BRCA2 act, may be inactivated by other means in sporadic tumors (ie, that they display BRCAness).46 If they share the DNA repair defect present in BRCA1- and BRCA2-deficient cells, they may also be candidates for the treatment strategies outlined in this review. BRCA1 hereditary tumors share many phenotypes with a subset of sporadic breast cancers called basal-like breast cancers.58,59 The similarity between basal-like breast cancers and BRCA1 hereditary tumors may suggest a common etiology, raising the possibility that basal-like cancers harbor an underlying defect in the BRCA1 pathway. Supporting evidence for the inactivation of BRCA1 in sporadic cancers comes from the finding that 10% to 15% of sporadic breast and ovarian cancers harbor BRCA1 promoter methylation.60 In many of these tumors, BRCA1 expression is undetectable, suggesting complete gene silencing and loss of BRCA1 function. However, it remains to be determined what proportion of these are causative of disease or a consequence of the disease state. It is currently unclear whether BRCA2 function is disrupted in sporadic cancers. The BRCA2 interacting protein EMSY is found in a commonly occurring breast cancer amplicon on chromosome 11q.61 Overexpression of EMSY may lead to inactivation of some of the functions of BRCA2, although it is not yet clear that this includes the DNA repair function of BRCA2. Additional possible mechanisms of inducing so-called BRCAness are methylation of the promoter of FANCF, a Fanconi Anemia gene, which has been reported in a number of sporadic cancers,62 and ataxia telangiectasia mutated (ATM) deficiency, which occurs in approximately 30% of chronic lymphocytic leukemias.63 Cells deficient in individual components of the Fanconi Anemia pathway or ATM are sensitive to PARP inhibitors.45 Currently, the treatments for cancers arising in carriers of BRCA1 or BRCA2 mutations are the same as for those occurring sporadically, matched for tumor pathology and age of onset. However, tumors in mutation carriers lack wild-type BRCA1 or BRCA2, but normal tissues retain a single wild-type copy of the relevant gene. This is a potentially targetable alteration that provides the basis for new mechanism-based approaches to the treatment of cancer. The biochemical difference in capacity to carry out HR between the tumor and normal tissues, in a BRCA1 or BRCA2 carrier, provides the rationale for this approach. Inhibiting the DNA repair protein PARP results in the generation of specific DNA lesions that require BRCA1 and BRCA2 specialized repair function(s) for their removal. Preclinical data indicate that tumors defective in wild-type BRCA1 or BRCA2 could be much more sensitive to PARP inhibition than unaffected heterozygous tissues, providing a potentially large therapeutic window. The safety and efficacy of this approach is currently being tested in clinical trials. Early indications are that these therapies show low toxicity, with some preliminary indications of activity. Synthetic lethality by combinatorial targeting of DNA repair pathways may have usefulness as a therapeutic approach beyond familial cancers. The majority of solid tumors also exhibit genomic instability and aneuploidy. This suggests that pathways involved in the maintenance of genomic stability are dysfunctional in a significant proportion of neoplastic disorders.64 Understanding which specialized DNA damage response and repair pathways are abrogated in sporadic tumor subtypes may allow the development of therapies that target the residual repair pathways on which the cancer, but not normal tissue, is now completely dependent. These potential therapies may significantly improve response rates while causing fewer treatment-related toxicities. However, these approaches may be associated with mechanism-associated resistance, and careful consideration of their optimal use will be required.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: Alan Ashworth, Co-inventor on patents relating to PARP inhibitors
published online ahead of print at www.jco.org on June 30, 2008. Supported by Cancer Research UK and Breakthrough Breast Cancer. Disclaimer: A.A. is a named co-inventor on patents relating to the use of PARP inhibitors and may benefit financially under the Institute of Cancer Research Rewards to Inventors scheme. Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Nature 396:643-649, 1998[CrossRef][Medline] Submitted January 4, 2008; accepted April 14, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
