Biomarker-Guided Development of DNA Repair Inhibitors
2020; Elsevier BV; Volume: 78; Issue: 6 Linguagem: Inglês
10.1016/j.molcel.2020.04.035
ISSN1097-4164
AutoresJames M. Cleary, Andrew J. Aguirre, Geoffrey I. Shapiro, Alan D. D’Andrea,
Tópico(s)Cancer therapeutics and mechanisms
ResumoAnti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies. Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies. The maintenance of genomic stability requires a protective cellular response to DNA-damaging agents. Genomic instability, which is a hallmark of cancer cells, results from a defect in this DNA damage response (DDR). The DDR pathway is an intricately regulated system designed to protect cells against acquired changes to the genome and has evolved to safeguard against intrinsic and extrinsic DNA damage. This pathway encompasses proteins that detect DNA damage, function in DNA repair pathways, and regulate the cell cycle. Oncologists have been therapeutically targeting the DDR pathway for decades with cytotoxic agents. Not surprisingly, many of the mechanisms of sensitivity and resistance to cytotoxic chemotherapy are governed by the DDR pathway. In recent years, new anti-cancer drugs have been generated that inhibit the regulatory pathways governing the DDR response (Table 1). This review will summarize progress made in targeting the DDR pathway and highlight efforts to rationally combine these drugs utilizing biomarkers that predict their sensitivity and resistance.Table 1DDR Inhibitors in Past or Present Clinical EvaluationPARP InhibitorsCHK1 InhibitorsATR InhibitorsDNA-PK InhibitorsWEE1 InhibitorATM InhibitorsNiraparib (MK-4827)aFDA approved.GDC-0575Ceralasertib (AZD6738)AZD7648Adavosertib (AZD1775)AZD0156Olaparib (AZD-2281)aFDA approved.LY3300054BAY1895344CC-115M3541Talazoparib (BMN-673)aFDA approved.MK-8776 (SCH-900776)Berzosertib (M6620, VX-970)M9831 (VX-984)Rucaparib (AG-014699)aFDA approved.Prexasertib (LY2606368)M4344 (VX-803)Nedisertib (M3814)Pamiparib (BGB-290)SRA-737 (CCT245737)Veliparib (ABT-888)AZD7762bNo longer in clinical trials.CEP-9722bNo longer in clinical trials.E7016 (GPI-21016)bNo longer in clinical trials.INO-1001bNo longer in clinical trials.a FDA approved.b No longer in clinical trials. Open table in a new tab The anti-cancer efficacy of cytotoxic chemotherapy and radiation is derived from their ability to damage DNA. Analysis of the molecular mechanism of how these treatments damage DNA, and are subsequently repaired, has increased our understanding of the DDR pathway and has exposed potential weakness that can be exploited with molecularly targeted therapies. For example, DNA damage caused by the alkylating chemotherapy temozolomide (TMZ), which is commonly used in glioblastoma and pancreatic neuroendocrine tumors, is repaired by MGMT (methylguanine methyltransferase). This finding provides a rationale for generating pharmacological inhibitors of MGMT that may further sensitize tumors to TMZ. To date, the clinical utilization of MGMT inhibitors, such as O6-benzylguanine, has been hampered by significant myelosuppression (Quinn et al., 2009Quinn J.A. Jiang S.X. Reardon D.A. Desjardins A. Vredenburgh J.J. Rich J.N. Gururangan S. Friedman A.H. Bigner D.D. Sampson J.H. et al.Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.J. Clin. Oncol. 2009; 27: 1262-1267Crossref PubMed Scopus (191) Google Scholar). Cisplatin mainly exerts damage on DNA by forming intrastrand crosslinks, with the formation of guanine-platinum-guanine and guanine-platinum-adenine adducts (Rocha et al., 2018Rocha C.R.R. Silva M.M. Quinet A. Cabral-Neto J.B. Menck C.F.M. DNA repair pathways and cisplatin resistance: an intimate relationship.Clinics (São Paulo). 2018; 73 (e478s–e478s)Crossref Scopus (32) Google Scholar). While ∼90% of the crosslinks formed by cisplatin are intrastrand, rarely, cisplatin can also generate guanine-platinum-guanine interstrand crosslinks (Rocha et al., 2018Rocha C.R.R. Silva M.M. Quinet A. Cabral-Neto J.B. Menck C.F.M. DNA repair pathways and cisplatin resistance: an intimate relationship.Clinics (São Paulo). 2018; 73 (e478s–e478s)Crossref Scopus (32) Google Scholar). Intrastrand DNA crosslinks are repaired by nucleotide excision repair (NER), a mechanism of single-strand DNA (ssDNA) repair that is deficient in patients with xeroderma pigmentosum (Schärer, 2013Schärer O.D. Nucleotide excision repair in eukaryotes.Cold Spring Harb. Perspect. Biol. 2013; 5: a012609Crossref PubMed Scopus (293) Google Scholar). Consistent with this, deleterious mutations in an NER pathway helicase, ERRC2, are predictive of cisplatin sensitivity in bladder cancer patients (Van Allen et al., 2014Van Allen E.M. Mouw K.W. Kim P. Iyer G. Wagle N. Al-Ahmadie H. Zhu C. Ostrovnaya I. Kryukov G.V. O’Connor K.W. et al.Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma.Cancer Discov. 2014; 4: 1140-1153Crossref PubMed Scopus (274) Google Scholar). Repair of interstrand crosslinks, which can also be generated by mitomycin-C, requires both NER and homologous recombination (HR) (Damia and Broggini, 2019Damia G. Broggini M. Platinum resistance in ovarian cancer: role of DNA repair.Cancers (Basel). 2019; 11: 119Crossref PubMed Scopus (0) Google Scholar, Rocha et al., 2018Rocha C.R.R. Silva M.M. Quinet A. Cabral-Neto J.B. Menck C.F.M. DNA repair pathways and cisplatin resistance: an intimate relationship.Clinics (São Paulo). 2018; 73 (e478s–e478s)Crossref Scopus (32) Google Scholar). Radiation is a particularly effective anti-cancer therapy, because it can sever covalent bonds in the DNA phosphodiester backbone and generate double-strand DNA breaks (Toulany, 2019Toulany M. Targeting DNA double-strand break repair pathways to improve radiotherapy response.Genes (Basel). 2019; 10: 25Crossref Scopus (17) Google Scholar). Bleomycin, a chemotherapy used in the treatment of testicular cancer and Hodgkin’s lymphoma, forms a complex with Fe2+ and O2 and can thereby cleave DNA and generate double-strand DNA breaks (Chen et al., 2008Chen J. Ghorai M.K. Kenney G. Stubbe J. Mechanistic studies on bleomycin-mediated DNA damage: multiple binding modes can result in double-stranded DNA cleavage.Nucleic Acids Res. 2008; 36: 3781-3790Crossref PubMed Scopus (0) Google Scholar). Topoisomerase I and II enzymes reduce DNA supercoiling by transiently causing single or double-strand DNA breaks, respectively, to allow DNA unwinding. Topoisomerase I inhibitors, such as irinotecan and topotecan, stabilize the topoisomerase I/DNA cleavage complex and prevent the closure of the ssDNA break (Pommier et al., 2010Pommier Y. Leo E. Zhang H. Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.Chem. Biol. 2010; 17: 421-433Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar). Likewise, topoisomerase II inhibitors, like etoposide and doxorubicin, trap the topoisomerase II/DNA cleavage complex and thereby generate a double-strand DNA break (Pommier et al., 2010Pommier Y. Leo E. Zhang H. Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.Chem. Biol. 2010; 17: 421-433Abstract Full Text Full Text PDF PubMed Scopus (1054) Google Scholar). The two canonical pathways of double-strand DNA break repair are HR and classical non-homologous end joining (cNHEJ). HR is preferred because of its high fidelity in repairing the genome. In contrast, cNHEJ utilizes nonspecific ligation to correct DNA breaks, resulting in error-prone repair (Chang et al., 2017Chang H.H.Y. Pannunzio N.R. Adachi N. Lieber M.R. Non-homologous DNA end joining and alternative pathways to double-strand break repair.Nat. Rev. Mol. Cell Biol. 2017; 18: 495-506Crossref PubMed Scopus (302) Google Scholar). The process of V(D)J recombination in immune cells advantageously harnesses the high percentage of errors introduced by cNHEJ to generate a diverse array of antibodies and T cell receptors. cNHEJ leads to characteristic DNA damage lesions, such as large deletions, resulting in loss of heterozygosity (LOH) and telomeric allelic imbalance. This error pattern can generate a highly recognizable genomic scar in HR-deficient cells, thus yielding an opportunity for therapeutic biomarker development (Table 2). Mechanistically, a key step in cNHEJ is the binding of KU70 and KU80 to the DNA (Chang et al., 2017Chang H.H.Y. Pannunzio N.R. Adachi N. Lieber M.R. Non-homologous DNA end joining and alternative pathways to double-strand break repair.Nat. Rev. Mol. Cell Biol. 2017; 18: 495-506Crossref PubMed Scopus (302) Google Scholar). This event activates DNA-dependent protein kinase (DNA-PK), which in turn activates a multi-protein complex of XRCC4, Artemis, and DNA ligase. The importance of DNA-PK, a phosphatidylinositol 3-kinase (PI3K)-related protein kinase, has driven the development of several DNA-PK inhibitors, including nedisertib (M3814), AZD7648, and M9831 (VX-984) (Blackford and Jackson, 2017Blackford A.N. Jackson S.P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response.Mol. Cell. 2017; 66: 801-817Abstract Full Text Full Text PDF PubMed Google Scholar: Table 1).Table 2Predictive and PD Biomarkers of DNA Repair InhibitorsDrugTargetPredictive MarkerPD MarkeraPD markers are a metric of target and/or pathway engagement.PARP inhibitorHRDHR gene mutation↑γH2AXHRD score (LOH), Signature 3↓PARylationUnstable replication forkbUnstable replications forks are evaluated in the laboratory with DNA fiber assays.↑Polθ↑Rad51 (in HR-proficient cells)cRAD51 foci increase in HR-proficient cells. RAD51 foci are absent in HR-deficient cells.Platinum sensitivity, Absent RAD51 foci↓Monoubiquitination of FANCD2DNA-PK inhibitorcNHEJLoss of Polθ or FEN1ATR inhibitorRS4ATM deficiency↓pCHK1RS promoting genomic changesdReplicative stress (RS)-promoting genomic changes include CCNE1 and MYC amplification and FBXW7 mutations.↑γH2AXUnstable replication fork↑Unstable replication fork↑pRPA, ↑pKAP1 RNase H2deficiency↑pKAP1CHK1 inhibitorRSp53 deficiency↑γH2AXRS promoting genomic changesdReplicative stress (RS)-promoting genomic changes include CCNE1 and MYC amplification and FBXW7 mutations.↑pCHK1Unstable replication fork↑Unstable replication fork↑pRPA, ↑pKAP1↑pRPA, ↑pKAP1WEE1 inhibitorRSp53 deficiencyRS promoting genomic changesdReplicative stress (RS)-promoting genomic changes include CCNE1 and MYC amplification and FBXW7 mutations.↑pCHK1↑γH2AXUnstable replication fork↑Unstable replication fork↑pRPA, ↑pKAP1↑pRPA↓pCDK1 (pCDC2)Polθ inhibitorAlt-EJHR deficiencyePolθ shares the same predictive biomarkers as PARP inhibitors.↑Rad51↑Polθ↑γH2AX↓cNHEJ↑Rad51 (in HR-proficient cells)a PD markers are a metric of target and/or pathway engagement.b Unstable replications forks are evaluated in the laboratory with DNA fiber assays.c RAD51 foci increase in HR-proficient cells. RAD51 foci are absent in HR-deficient cells.d Replicative stress (RS)-promoting genomic changes include CCNE1 and MYC amplification and FBXW7 mutations.e Polθ shares the same predictive biomarkers as PARP inhibitors. Open table in a new tab Unlike cNHEJ, HR uses a template from a sister chromatid to achieve accurate DNA repair. While cNHEJ can occur at any time in the cell cycle, HR occurs only in the S and G2 phases. A trio of three proteins, MRE11-RAD50-NBS1 (also called the MRN complex), initiates the pathway by binding to double-strand DNA breaks (Ranjha et al., 2018Ranjha L. Howard S.M. Cejka P. Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes.Chromosoma. 2018; 127: 187-214Crossref PubMed Scopus (63) Google Scholar). The MRN complex, in concert with the carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) endonuclease and BRCA1, mediates DNA end resection. In addition, the MRN complex activates ataxia-telangiectasia mutated (ATM), which leads to the activation of BRCA1, BRCA2, and PALB2. Following this event, RAD51 loads at the sites of DNA damage and results in the formation of a nucleoprotein filament that then invades the sister chromatid to find homologous DNA sequences that serve as a template for the synthesis of new DNA. Inhibitors of ATM and RAD51 are currently under development. The HR pathway is deficient in Fanconi anemia (FA), a rare genetic disease leading to bone marrow failure and increased cancer risk. Tumor cells with a deficiency in the FA/BRCA pathway are hypersensitive to chemotherapies that cause DNA interstrand crosslinks, such as mitomycin-C and cisplatin, and, in some cases, to poly (ADP-ribose) polymerase (PARP) inhibitors (Table 2). Cells from FA patients also demonstrate chromosomal instability. Indeed, the BRCA2 breast cancer susceptibility gene was previously mapped to the FANCD1 complementation group (Howlett et al., 2002Howlett N.G. Taniguchi T. Olson S. Cox B. Waisfisz Q. De Die-Smulders C. Persky N. Grompe M. Joenje H. Pals G. et al.Biallelic inactivation of BRCA2 in Fanconi anemia.Science. 2002; 297: 606-609Crossref PubMed Scopus (898) Google Scholar), thereby establishing the so-called FA/BRCA pathway. PARP inhibitors capitalize on the HR deficiency (HRD) of many cancers in part by inhibiting other DNA repair pathways such as base excision repair (BER). While PARP inhibitors target tumors with intrinsic HRD, additional therapies are under development to inhibit HR in tumors. For example, a first-in-class RAD51 inhibitor, CYT01B, can block HR and has demonstrated preclinical activity in cancer cells expressing activation-induced cytidine deaminase (AID), a protein promoting double-strand DNA breaks (Maclay et al., 2018Maclay T. Vacca J. McComas C. Castro A. Day M. Mills K. CYT01B, a novel RAD51 inhibitor, act synergistically with both targeted and chemotherapeutic anti-cancer agents.Blood. 2018; 132 (3963–3963)Crossref Google Scholar). Importantly, CYT01B synergizes with PARP and ataxia-telangiectasia and Rad3-related (ATR) inhibitors in model systems (Maclay et al., 2018Maclay T. Vacca J. McComas C. Castro A. Day M. Mills K. CYT01B, a novel RAD51 inhibitor, act synergistically with both targeted and chemotherapeutic anti-cancer agents.Blood. 2018; 132 (3963–3963)Crossref Google Scholar). Unlike cNHEJ, HR requires the generation of a ssDNA 3′ overhang at the end of a double-strand DNA break in a process known as end resection. The tumor suppressor p53-binding protein 1 (53BP1) and the shieldin complex, made up of the SHLD1, SHLD2, SHLD3, and REV7 proteins, blocks end resection (Noordermeer et al., 2018Noordermeer S.M. Adam S. Setiaputra D. Barazas M. Pettitt S.J. Ling A.K. Olivieri M. Álvarez-Quilón A. Moatti N. Zimmermann M. et al.The shieldin complex mediates 53BP1-dependent DNA repair.Nature. 2018; 560: 117-121Crossref PubMed Scopus (225) Google Scholar). By preventing formation of a ssDNA 3′ overhang, these proteins promote cNHEJ. Importantly, regulation of this complex plays a key role in determining whether double-strand DNA breaks are repaired by HR or cNHEJ. BRCA1 and 53BP1 play opposing roles in determining whether HR or cNHEJ is utilized (Escribano-Díaz et al., 2013Escribano-Díaz C. Orthwein A. Fradet-Turcotte A. Xing M. Young J.T. Tkáč J. Cook M.A. Rosebrock A.P. Munro M. Canny M.D. et al.A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.Mol. Cell. 2013; 49: 872-883Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar). BRCA1 stimulates the MRN complex to activate CtIP-mediated 5′ to 3′ end resection to promote HR (Makharashvili and Paull, 2015Makharashvili N. Paull T.T. CtIP: a DNA damage response protein at the intersection of DNA metabolism.DNA Repair (Amst.). 2015; 32: 75-81Crossref PubMed Scopus (46) Google Scholar). Notably, in S phase, BRCA1 activation also leads to decreased amounts of 53BP1 on chromatin (Chapman et al., 2012Chapman J.R. Sossick A.J. Boulton S.J. Jackson S.P. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair.J. Cell Sci. 2012; 125: 3529-3534Crossref PubMed Scopus (168) Google Scholar, Escribano-Díaz et al., 2013Escribano-Díaz C. Orthwein A. Fradet-Turcotte A. Xing M. Young J.T. Tkáč J. Cook M.A. Rosebrock A.P. Munro M. Canny M.D. et al.A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.Mol. Cell. 2013; 49: 872-883Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar, Isono et al., 2017Isono M. Niimi A. Oike T. Hagiwara Y. Sato H. Sekine R. Yoshida Y. Isobe S.Y. Obuse C. Nishi R. et al.BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation.Cell Rep. 2017; 18: 520-532Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). However, in G1, 53BP1 and its effector protein, RIF1, prevent end resection by promoting the assembly of the shieldin complex and activating NHEJ (Chapman et al., 2012Chapman J.R. Sossick A.J. Boulton S.J. Jackson S.P. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair.J. Cell Sci. 2012; 125: 3529-3534Crossref PubMed Scopus (168) Google Scholar, Escribano-Díaz et al., 2013Escribano-Díaz C. Orthwein A. Fradet-Turcotte A. Xing M. Young J.T. Tkáč J. Cook M.A. Rosebrock A.P. Munro M. Canny M.D. et al.A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.Mol. Cell. 2013; 49: 872-883Abstract Full Text Full Text PDF PubMed Scopus (476) Google Scholar). TRIP13 is an ATPase that inactivates the shieldin complex and activates the 5′ to 3′ resection of double-strand breaks, thereby promoting HR repair (Clairmont et al., 2020Clairmont C.S. Sarangi P. Ponnienselvan K. Galli L.D. Csete I. Moreau L. Adelmant G. Chowdhury D. Marto J.A. D’Andrea A.D. TRIP13 regulates DNA repair pathway choice through REV7 conformational change.Nat. Cell Biol. 2020; 22: 87-96Crossref PubMed Scopus (8) Google Scholar). Importantly, TRIP13 is amplified in many BRCA1-deficient tumors, and its upregulation may contribute to the intrinsic PARP inhibitor resistance of many of these tumors. Accordingly, a small-molecule inhibitor of the ATPase domain of TRIP13 may provide a useful means of stabilizing the shieldin complex, promoting cNHEJ, blocking HR, and overcoming intrinsic PARP inhibitor resistance. Early studies suggest that development of TRIP13 inhibitors may be useful not only in the treatment of BRCA1-deficient tumor cells with intrinsic PARP inhibitor resistance but also in tumors with acquired PARP inhibitor resistance (Clairmont et al., 2020Clairmont C.S. Sarangi P. Ponnienselvan K. Galli L.D. Csete I. Moreau L. Adelmant G. Chowdhury D. Marto J.A. D’Andrea A.D. TRIP13 regulates DNA repair pathway choice through REV7 conformational change.Nat. Cell Biol. 2020; 22: 87-96Crossref PubMed Scopus (8) Google Scholar). The elucidation of a third mechanism of DSB repair has identified important new DDR drug targets. This mechanism, called alternative nonhomologous end joining (Alt-EJ) or microhomology-mediated end joining (MMEJ), requires “microhomology” (i.e., homologous DNA sequences ∼2–20 bp in length) at the DNA break points (Bennardo et al., 2008Bennardo N. Cheng A. Huang N. Stark J.M. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair.PLoS Genet. 2008; 4: e1000110Crossref PubMed Scopus (459) Google Scholar, Ranjha et al., 2018Ranjha L. Howard S.M. Cejka P. Main steps in DNA double-strand break repair: an introduction to homologous recombination and related processes.Chromosoma. 2018; 127: 187-214Crossref PubMed Scopus (63) Google Scholar). Importantly, Alt-EJ is dependent on PARP1. Following binding of the double-strand break by the MRN complex and PARP1, Polymeraseθ (Polθ) mediates the repair of the break. While the alt-EJ repair system is used rarely in HR proficient tumors, HRD results in increased dependency on alt-EJ (Ceccaldi et al., 2015Ceccaldi R. Liu J.C. Amunugama R. Hajdu I. Primack B. Petalcorin M.I. O’Connor K.W. Konstantinopoulos P.A. Elledge S.J. Boulton S.J. et al.Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair.Nature. 2015; 518: 258-262Crossref PubMed Scopus (288) Google Scholar). The dependence of alt-EJ on Polθ suggests that Polθ inhibitors may be effective for HR-deficient tumors. The final type of DSB repair is termed single-strand annealing. Similar to Alt-EJ, single strand-annealing requires homologous DNA sites to catalyze the repair of the double-strand break (Bhargava et al., 2016Bhargava R. Onyango D.O. Stark J.M. Regulation of single-strand annealing and its role in genome maintenance.Trends Genet. 2016; 32: 566-575Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). However, unlike Alt-EJ, single-strand annealing can take place over long stretches of DNA and lead to large deletions that can cause intrachromosomal translocations. Mechanistically, single-strand annealing is inhibited by RAD51 (Stark et al., 2004Stark J.M. Pierce A.J. Oh J. Pastink A. Jasin M. Genetic steps of mammalian homologous repair with distinct mutagenic consequences.Mol. Cell. Biol. 2004; 24: 9305-9316Crossref PubMed Scopus (320) Google Scholar). Unlike Alt-EJ, which requires PARP and Polθ, single-strand annealing requires RAD52 to marshal the annealing of the homologous stretches of ssDNA (Bennardo et al., 2008Bennardo N. Cheng A. Huang N. Stark J.M. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair.PLoS Genet. 2008; 4: e1000110Crossref PubMed Scopus (459) Google Scholar, Grimme et al., 2010Grimme J.M. Honda M. Wright R. Okuno Y. Rothenberg E. Mazin A.V. Ha T. Spies M. Human Rad52 binds and wraps single-stranded DNA and mediates annealing via two hRad52-ssDNA complexes.Nucleic Acids Res. 2010; 38: 2917-2930Crossref PubMed Scopus (74) Google Scholar). Two seminal papers introduced the concept that PARP inhibitors have synthetic lethal interaction with HR-deficient tumors (Bryant et al., 2005Bryant H.E. Schultz N. Thomas H.D. Parker K.M. Flower D. Lopez E. Kyle S. Meuth M. Curtin N.J. Helleday T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (2809) Google Scholar, Farmer et al., 2005Farmer H. McCabe N. Lord C.J. Tutt A.N.J. Johnson D.A. Richardson T.B. Santarosa M. Dillon K.J. Hickson I. Knights C. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (3654) Google Scholar; Figure 1). PARP1 binding to ssDNA breaks generated in BER forms a foundation of the synthetic lethal interaction with HRD (De Vos et al., 2012De Vos M. Schreiber V. Dantzer F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art.Biochem. Pharmacol. 2012; 84: 137-146Crossref PubMed Scopus (297) Google Scholar, Ström et al., 2011Ström C.E. Johansson F. Uhlén M. Szigyarto C.A. Erixon K. Helleday T. Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate.Nucleic Acids Res. 2011; 39: 3166-3175Crossref PubMed Scopus (179) Google Scholar). When BER cannot repair ssDNA breaks, the single-strand breaks ultimately become double-strand DNA breaks. While HR-proficient cells can rely on the HR repair to correct double-strand DNA breaks, HR-deficient cells are forced to rely on cNHEJ (McCabe et al., 2006McCabe N. Turner N.C. Lord C.J. Kluzek K. Bialkowska A. Swift S. Giavara S. O’Connor M.J. Tutt A.N. Zdzienicka M.Z. et al.Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.Cancer Res. 2006; 66: 8109-8115Crossref PubMed Scopus (819) Google Scholar). However, the error-prone nature of cNHEJ ultimately leads to genomic instability and cell death (Patel et al., 2011Patel A.G. Sarkaria J.N. Kaufmann S.H. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells.Proc. Natl. Acad. Sci. USA. 2011; 108: 3406-3411Crossref PubMed Scopus (313) Google Scholar). Preclinical and clinical studies of PARP inhibitors soon revealed additional mechanisms of PARP inhibitor activity. PARP inhibitors have been shown to “trap” the PARP enzyme at the site of DNA damage, therefore preventing essential cellular processes such as DNA repair and transcription. Furthermore, the trapped PARP-DNA complex is particularly lethal in HR-deficient cells. Multiple studies have demonstrated differential potency of different PARP inhibitors. In HR-deficient cell lines, the half maximal inhibitory concentration (IC50) of talazoparib (5 nM) was significantly lower than that of olaparib (259 nM), rucaparib (609 nM), and veliparib (>10,000 nM) (Shen et al., 2013Shen Y. Rehman F.L. Feng Y. Boshuizen J. Bajrami I. Elliott R. Wang B. Lord C.J. Post L.E. Ashworth A. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency.Clin. Cancer Res. 2013; 19: 5003-5015Crossref PubMed Scopus (263) Google Scholar). One explanation for the increased potency of talazoparib is its strong PARP trapping activity (∼100-fold greater than that of other PARP inhibitors) (Murai et al., 2014aMurai J. Huang S.-Y.N. Renaud A. Zhang Y. Ji J. Takeda S. Morris J. Teicher B. Doroshow J.H. Pommier Y. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.Mol. Cancer Ther. 2014; 13: 433-443Crossref PubMed Scopus (318) Google Scholar). Similarly, the relatively weak PARP trapping of veliparib may account for its weaker anti-cancer activity compared to other PARP inhibitors (Murai et al., 2012Murai J. Huang S.Y. Das B.B. Renaud A. Zhang Y. Doroshow J.H. Ji J. Takeda S. Pommier Y. Trapping of PARP1 and PARP2 by clinical PARP inhibitors.Cancer Res. 2012; 72: 5588-5599Crossref PubMed Scopus (835) Google Scholar). Clinical trials of PARP inhibitors have led to their approval by the United States Food and Drug Administration (FDA) in several indications, including ovarian, breast, and pancreatic cancer (Table 1; Geenen et al., 2018Geenen J.J.J. Linn S.C. Beijnen J.H. Schellens J.H.M. PARP inhibitors in the treatment of triple-negative breast cancer.Clin. Pharmacokinet. 2018; 57: 427-437Crossref PubMed Scopus (14) Google Scholar, Golan et al., 2019Golan T. Hammel P. Reni M. Van Cutsem E. Macarulla T. Hall M.J. Park J.-O. Hochhauser D. Arnold D. Oh D.-Y. et al.Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 2019; 381: 317-327Crossref PubMed Scopus (0) Google Scholar, Konstantinopoulos and Matulonis, 2018Konstantinopoulos P.A. Matulonis U.A. PARP inhibitors in ovarian cancer: a trailblazing and transformative journey.Clin. Cancer Res. 2018; 24: 4062-4065Crossref PubMed Scopus (11) Google Scholar). The anti-cancer efficacy and favorable side effect profile of PARP inhibitors has led to their rapid adoption into clinical practice. While myelosuppression can be a limiting toxicity, these orally administered drugs are generally well tolerated, with most patients reporting minimal symptomatic PARP-inhibitor-induced toxicities. In recent years, there has been growing appreciation for the role of the Alt-EJ system in double-strand DNA repair (Bennardo et al., 2008Bennardo N. Cheng A. Huang N. Stark J.M. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair.PLoS Genet. 2008; 4: e1000110Crossref PubMed Scopus (459) Google Scholar, Wood and Doublié, 2016Wood R.D. Doublié S. DNA polymerase θ (POLQ), double-strand break repair, and cancer.DNA Repair (Amst.). 2016; 44: 22-32Crossref PubMed Scopus (56) Google Scholar). Mice deficient in polymerase Polθ are viable and exhibit a mild phenot
Referência(s)