Targeting the DNA Damage Response in Cancer
2015; Elsevier BV; Volume: 60; Issue: 4 Linguagem: Inglês
10.1016/j.molcel.2015.10.040
ISSN1097-4164
Autores Tópico(s)Cell death mechanisms and regulation
ResumoAn underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles’ heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future. An underlying hallmark of cancers is their genomic instability, which is associated with a greater propensity to accumulate DNA damage. Historical treatment of cancer by radiotherapy and DNA-damaging chemotherapy is based on this principle, yet it is accompanied by significant collateral damage to normal tissue and unwanted side effects. Targeted therapy based on inhibiting the DNA damage response (DDR) in cancers offers the potential for a greater therapeutic window by tailoring treatment to patients with tumors lacking specific DDR functions. The recent approval of olaparib (Lynparza), the poly (ADP-ribose) polymerase (PARP) inhibitor for treating tumors harboring BRCA1 or BRCA2 mutations, represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles’ heel. This review highlights the different concepts behind targeting DDR in cancer and how this can provide significant opportunities for DDR-based therapies in the future. Tens of thousands of DNA damage events occur every day in our cells, and many different mechanisms have evolved to deal with them (Ciccia and Elledge, 2010Ciccia A. Elledge S.J. The DNA damage response: making it safe to play with knives.Mol. Cell. 2010; 40: 179-204Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar, Jackson and Bartek, 2009Jackson S.P. Bartek J. The DNA-damage response in human biology and disease.Nature. 2009; 461: 1071-1078Crossref PubMed Scopus (1133) Google Scholar). The DNA damage response (DDR) is a collective term for the plethora of different intra- and inter-cellular signaling events and enzyme activities that result from the induction and detection of DNA damage. These include events that lead to cell-cycle arrest, regulation of DNA replication, and the repair or bypass of DNA damage. Should DNA repair not be possible or suboptimal repair lead to an unsupportable level of genomic instability, DDR can also impact on downstream cell fate decisions, such as cell death or senescence that can either be dependent or independent of the immune system (d’Adda di Fagagna et al., 2003d’Adda di Fagagna F. Reaper P.M. Clay-Farrace L. Fiegler H. Carr P. Von Zglinicki T. Saretzki G. Carter N.P. Jackson S.P. A DNA damage checkpoint response in telomere-initiated senescence.Nature. 2003; 426: 194-198Crossref PubMed Scopus (1220) Google Scholar, Freund et al., 2010Freund A. Orjalo A.V. Desprez P.Y. Campisi J. Inflammatory networks during cellular senescence: causes and consequences.Trends Mol. Med. 2010; 16: 238-246Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Kang et al., 2015Kang C. Xu Q. Martin T.D. Li M.Z. Demaria M. Aron L. Lu T. Yankner B.A. Campisi J. Elledge S.J. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.Science. 2015; 349: aaa5612Crossref PubMed Scopus (1) Google Scholar). Recent analyses suggest that there are at least 450 proteins integral to DDR (Pearl et al., 2015Pearl L.H. Schierz A.C. Ward S.E. Al-Lazikani B. Pearl F.M. Therapeutic opportunities within the DNA damage response.Nat. Rev. Cancer. 2015; 15: 166-180Crossref PubMed Scopus (3) Google Scholar), and the choice of optimal drug target within DDR will be based on what type of DNA damage repair is to be inhibited and when in the cell cycle that damage is likely to occur (Figure 1). Different forms of DNA damage evoke responses by different repair mechanisms and signaling pathways (Hoeijmakers, 2001Hoeijmakers J.H. Genome maintenance mechanisms for preventing cancer.Nature. 2001; 411: 366-374Crossref PubMed Scopus (2151) Google Scholar), and while there is not an absolute redundancy as such, different DDR pathways may potentially compensate in the absence of the optimal or bespoke repair pathway. An analogy might be carpentry tools where, in the absence of a specific tool for a repair job, another tool can be used, although that tool may not be quite as effective and the results not quite so accurate. In human cells there are five major repair pathways. Modified bases, abasic sites, and the DNA single-strand breaks (SSBs) primarily generated from their processing are the most common form of DNA damage, estimated at more than 20,000 events per cell per day (Lindahl et al., 1995Lindahl T. Satoh M.S. Poirier G.G. Klungland A. Post-translational modification of poly(ADP-ribose) polymerase induced by DNA strand breaks.Trends Biochem. Sci. 1995; 20: 405-411Abstract Full Text PDF PubMed Scopus (476) Google Scholar), and these are repaired by the base excision repair (BER) pathway (Caldecott, 2014Caldecott K.W. DNA single-strand break repair.Exp. Cell Res. 2014; 329: 2-8Crossref PubMed Scopus (10) Google Scholar, Wilson et al., 2010Wilson S.H. Beard W.A. Shock D.D. Batra V.K. Cavanaugh N.A. Prasad R. Hou E.W. Liu Y. Asagoshi K. Horton J.K. et al.Base excision repair and design of small molecule inhibitors of human DNA polymerase β.Cell. Mol. Life Sci. 2010; 67: 3633-3647Crossref PubMed Scopus (17) Google Scholar). There are two major forms of repair when dealing with DNA double-strand breaks (DSBs) (Shibata and Jeggo, 2014Shibata A. Jeggo P.A. DNA double-strand break repair in a cellular context.Clin. Oncol. (R Coll Radiol). 2014; 26: 243-249Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), the most genotoxic form of DNA lesion due to the issues associated with accurate chromosome segregation during cell division. Homologous recombination repair (HRR) is a relatively accurate and efficient repair pathway but depends upon the presence of undamaged sister chromatid DNA (Moynahan and Jasin, 2010Moynahan M.E. Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis.Nat. Rev. Mol. Cell Biol. 2010; 11: 196-207Crossref PubMed Scopus (291) Google Scholar), while the non-homologous end-joining (NHEJ) pathways (C-NHEJ and alt-NHEJ) are not dependent on the presence of replicated DNA and, while still effective, are less accurate, potentially introducing DNA rearrangements (Ceccaldi et al., 2015Ceccaldi R. Rondinelli B. D’Andrea A.D. Repair Pathway Choices and Consequences at the Double-Strand Break.Trends Cell Biol. 2015; https://doi.org/10.1016/j.tcb.2015.07.009Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Lieber, 2010Lieber M.R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway.Annu. Rev. Biochem. 2010; 79: 181-211Crossref PubMed Scopus (597) Google Scholar, Radhakrishnan et al., 2014Radhakrishnan S.K. Jette N. Lees-Miller S.P. Non-homologous end joining: emerging themes and unanswered questions.DNA Repair (Amst.). 2014; 17: 2-8Crossref PubMed Scopus (0) Google Scholar). The nucleotide excision repair (NER) pathway deals with modified nucleotides that distort the structure of the double helix (Hoeijmakers, 2009Hoeijmakers J.H. DNA damage, aging, and cancer.N. Engl. J. Med. 2009; 361: 1475-1485Crossref PubMed Scopus (486) Google Scholar) and is the pathway that primarily deals with UV-induced damage but also plays an important role in dealing with DNA damage induced by platinum salts as well. The mismatch repair (MMR) pathway deals with replication errors, including mismatch base-pairing as well as nucleotide insertions and deletions (Jiricny, 2006Jiricny J. The multifaceted mismatch-repair system.Nat. Rev. Mol. Cell Biol. 2006; 7: 335-346Crossref PubMed Scopus (525) Google Scholar). Another common event during the replication process is the incorporation of ribonucleotides. Removal by RNase H2 prevents the increased likelihood of DNA strand breaks that would otherwise form due to the greater susceptibility of ribonucleotides to hydrolysis compared with deoxynucleotides (Reijns et al., 2012Reijns M.A. Rabe B. Rigby R.E. Mill P. Astell K.R. Lettice L.A. Boyle S. Leitch A. Keighren M. Kilanowski F. et al.Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development.Cell. 2012; 149: 1008-1022Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). In addition to these major pathways, nucleotide damage in the form of adducts that can block replication fork progression, either occurring naturally through environmental mutagens or from chemotherapy such as platinum agents, can be bypassed as a short-term solution by a mechanism known as translesion synthesis (Goodman and Woodgate, 2013Goodman M.F. Woodgate R. Translesion DNA polymerases.Cold Spring Harb. Perspect. Biol. 2013; 5: a010363Crossref Scopus (17) Google Scholar, Waters et al., 2009Waters L.S. Minesinger B.K. Wiltrout M.E. D’Souza S. Woodruff R.V. Walker G.C. Eukaryotic translesion polymerases and their roles and regulation in DNA damage tolerance.Microbiol. Mol. Biol. Rev. 2009; 73: 134-154Crossref PubMed Scopus (220) Google Scholar). Other mechanisms of DNA damage tolerance that allow DNA replication to proceed in the presence of damage include convergence of adjacent replicons, discontinuous synthesis of Okazaki fragments on the lagging DNA strand, and re-priming of DNA synthesis downstream of lesions on the leading strand (Bianchi et al., 2013Bianchi J. Rudd S.G. Jozwiakowski S.K. Bailey L.J. Soura V. Taylor E. Stevanovic I. Green A.J. Stracker T.H. Lindsay H.D. Doherty A.J. PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication.Mol. Cell. 2013; 52: 566-573Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Heller and Marians, 2006Heller R.C. Marians K.J. Replication fork reactivation downstream of a blocked nascent leading strand.Nature. 2006; 439: 557-562Crossref PubMed Scopus (180) Google Scholar). DNA inter-strand cross-links that can also impair replication are repaired through the activities of the Fanconi anemia (FA) complex of proteins (Kee and D’Andrea, 2010Kee Y. D’Andrea A.D. Expanded roles of the Fanconi anemia pathway in preserving genomic stability.Genes Dev. 2010; 24: 1680-1694Crossref PubMed Scopus (152) Google Scholar). Finally, three common forms of base damage (O6-methylguanine, 1-methyladenine, and 3-methylcytosine) can be repaired directly (Sedgwick et al., 2007Sedgwick B. Bates P.A. Paik J. Jacobs S.C. Lindahl T. Repair of alkylated DNA: recent advances.DNA Repair (Amst.). 2007; 6: 429-442Crossref PubMed Scopus (139) Google Scholar). The response to DNA damage will be different depending on the cell-cycle status. For example, cells in G1 will not have sister chromatid DNA available as an undamaged template and therefore will be dependent upon NHEJ pathways for the repair of DSBs. In addition, there are important differences in the primary roles of checkpoints at different stages of the cell cycle and in the DDR factors that are involved. For example, the G1/S checkpoint allows the repair of DNA damage prior to the start of DNA replication in order to remove obstacles to DNA synthesis, and key DDR factors regulating this checkpoint include ATM, CHK2, and p53. The intra-S phase checkpoint proteins ATR, CHK1, DNA-PK, and WEE1 can delay replication origin firing to provide time to deal with any unrepaired DNA damage that has occurred, thus preventing under-replicated DNA regions being taken beyond S-phase. The activities of the G2/M checkpoint proteins including CHK1, MYT1, and WEE1 lead to an increase in phosphorylated CDK1, thereby keeping it in its inactive state and delaying mitotic entry. The G2/M checkpoint really represents the last major opportunity for preventing DNA damage being taken into mitosis where unrepaired DSBs and under-replicated DNA may result in mitotic catastrophe and cell death (Castedo et al., 2004Castedo M. Perfettini J.L. Roumier T. Andreau K. Medema R. Kroemer G. Cell death by mitotic catastrophe: a molecular definition.Oncogene. 2004; 23: 2825-2837Crossref PubMed Scopus (624) Google Scholar). Given the fundamental role of the DDR, one could be forgiven for wondering why DDR represents a good source of anticancer drug targets at all. The explanation lies in the fact that there are at least three key aspects of DDR that are different in cancers compared with normal cells, which in turn makes DDR an attractive source for drug targets that can (and indeed currently are) being exploited to generate new cancer therapies (Figure 2). The first aspect of cancer DDR that is different from normal cells is that most (if not all) cancers will have lost one or more DDR pathway or capability during their generation, leading to a greater dependency on the remaining pathways (Jackson and Bartek, 2009Jackson S.P. Bartek J. The DNA-damage response in human biology and disease.Nature. 2009; 461: 1071-1078Crossref PubMed Scopus (1133) Google Scholar). Figure 3 outlines the underlying concept as well as the opportunity for exploitation using DDR inhibitors. An early step in tumorigenesis is the deregulation of cell proliferation that can result, for example, from oncogenic stress (Hahn et al., 1999Hahn W.C. Counter C.M. Lundberg A.S. Beijersbergen R.L. Brooks M.W. Weinberg R.A. Creation of human tumour cells with defined genetic elements.Nature. 1999; 400: 464-468Crossref PubMed Scopus (1586) Google Scholar). This has been shown to lead to the activation of a DDR, particularly activation of ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and rad3-related (ATR) pathways, characterized by constitutive phosphorylation of ATM, CHK2, histone H2AX, and p53 (Bartkova et al., 2010Bartkova J. Hamerlik P. Stockhausen M.T. Ehrmann J. Hlobilkova A. Laursen H. Kalita O. Kolar Z. Poulsen H.S. Broholm H. et al.Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas.Oncogene. 2010; 29: 5095-5102Crossref PubMed Scopus (48) Google Scholar, Bartkova et al., 2005Bartkova J. Horejsí Z. Koed K. Krämer A. Tort F. Zieger K. Guldberg P. Sehested M. Nesland J.M. Lukas C. et al.DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.Nature. 2005; 434: 864-870Crossref PubMed Scopus (1479) Google Scholar, Gorgoulis et al., 2005Gorgoulis V.G. Vassiliou L.V. Karakaidos P. Zacharatos P. Kotsinas A. Liloglou T. Venere M. Ditullio Jr., R.A. Kastrinakis N.G. Levy B. et al.Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.Nature. 2005; 434: 907-913Crossref PubMed Scopus (1138) Google Scholar). While this activation of the DDR in precancerous cells has been proposed to represent a barrier to uncontrolled cell growth, in cells that have progressed to form tumors, this barrier will have been removed through loss of one or more DDR capabilities (Halazonetis et al., 2008Halazonetis T.D. Gorgoulis V.G. Bartek J. An oncogene-induced DNA damage model for cancer development.Science. 2008; 319: 1352-1355Crossref PubMed Scopus (692) Google Scholar). As a consequence, cancer cells demonstrate increased genomic instability and a greater dependency on remaining DDR pathways to deal with both endogenous and exogenous DNA damage. A cancer cell that harbors a DDR deficiency resulting in a dependency on a particular DDR target or pathway for survival in this way, provides the potential for single-agent activity of an inhibitor of that target or pathway—an approach that has been described as synthetic lethality (Ashworth, 2008Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair.J. Clin. Oncol. 2008; 26: 3785-3790Crossref PubMed Scopus (318) Google Scholar, Curtin, 2012Curtin N.J. DNA repair dysregulation from cancer driver to therapeutic target.Nat. Rev. Cancer. 2012; 12: 801-817Crossref PubMed Scopus (133) Google Scholar). The original context for synthetic lethality in Drosophila involved two genetic loss-of-function events, either of which alone was compatible with viability but together in the same cell resulted in lethality (Lucchesi, 1968Lucchesi J.C. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanfgaster.Genetics. 1968; 59: 37-44PubMed Google Scholar). The concept has been developed further with the idea that yeast could be used for the discovery of anticancer drugs by screening compounds in specifically defined genetic backgrounds (Hartwell et al., 1997Hartwell L.H. Szankasi P. Roberts C.J. Murray A.W. Friend S.H. Integrating genetic approaches into the discovery of anticancer drugs.Science. 1997; 278: 1064-1068Crossref PubMed Scopus (348) Google Scholar). In the context of DDR therapeutics illustrated in Figure 3, one event is genetic and specific to the tumor and not found in normal cells; the second loss-of-function event is achieved pharmacologically through treatment with a DDR inhibitor. This approach of targeting a gene product that is synthetic lethal to a cancer-relevant mutation is predicted to preferentially kill cancer cells and spare normal cells, providing a significant patient benefit over conventional cancer chemotherapeutic approaches (Curtin, 2012Curtin N.J. DNA repair dysregulation from cancer driver to therapeutic target.Nat. Rev. Cancer. 2012; 12: 801-817Crossref PubMed Scopus (133) Google Scholar, Kaelin, 2005Kaelin Jr., W.G. The concept of synthetic lethality in the context of anticancer therapy.Nat. Rev. Cancer. 2005; 5: 689-698Crossref PubMed Scopus (564) Google Scholar, Lord and Ashworth, 2012Lord C.J. Ashworth A. The DNA damage response and cancer therapy.Nature. 2012; 481: 287-294Crossref PubMed Scopus (281) Google Scholar, O’Connor et al., 2007O’Connor M.J. Martin N.M. Smith G.C. Targeted cancer therapies based on the inhibition of DNA strand break repair.Oncogene. 2007; 26: 7816-7824Crossref PubMed Scopus (83) Google Scholar). The realization of this prediction in the form of clinical validation has been provided by the recent regulatory approval of olaparib (Lynparza), the first poly (ADP ribose) polymerase or PARP inhibitor to market (EMA, 2014EMA (2014). Lynparza recommended for approval in ovarian cancer. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/10/news_detail_002196.jsp&mid=WC0b01ac058004d5c1.Google Scholar, FDA, 2015FDA (2015). FDA approves Lynparza to treat advanced ovarian cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm.Google Scholar). PARP is a major factor in the repair of SSBs, and the mechanism of action of inhibitors currently being developed in the clinic as a monotherapy (Table 1) involves the inhibition of PARP enzymatic activity (formation of poly ADP-ribose chains from NAD+) that is required for both relaxing chromatin and PARP dissociation from the DNA that occurs following auto-modification. Both of these events are required to facilitate SSB repair, and the structures of the PARP inhibitors are built around an NAD+ mimetic core. Consequently, competitive inhibition prevents NAD+ utilization on PARP protein that is bound to SSBs, preventing repair by trapping the inactivated enzyme onto the SSB and generating a potential block for cellular DNA replication (Helleday, 2011Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings.Mol. Oncol. 2011; 5: 387-393Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 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 (144) Google Scholar). An important consequence of this is that trapped PARP-DNA complexes can lead to the stalling and/or collapsing of replication forks, resulting in the generation of more deleterious DSBs (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 (144) Google Scholar). As described above, in replicating cells these DSBs would normally be repaired by HRR. In cancers with HRR deficiency (HRD), the use of lower fidelity forms of DNA repair such as NHEJ will result in a significant increase in genomic instability that over multiple rounds of replication will become unsustainable and result in tumor cell death (Ceccaldi et al., 2015Ceccaldi R. Rondinelli B. D’Andrea A.D. Repair Pathway Choices and Consequences at the Double-Strand Break.Trends Cell Biol. 2015; https://doi.org/10.1016/j.tcb.2015.07.009Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Mateos-Gomez et al., 2015Mateos-Gomez P.A. Gong F. Nair N. Miller K.M. Lazzerini-Denchi E. Sfeir A. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination.Nature. 2015; 518: 254-257Crossref PubMed Scopus (10) Google Scholar, 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 (112) Google Scholar) (Figure 4).Table 1DDR Inhibitors in Clinical DevelopmentPathwayTargetCompoundLatest Stage of Development and Trial DetailsClinical Trial Identifier(s)BERAPE1MethoxyaminePhase II in combination with TMZ in glioblastomaNCT02395692PARPE7016Phase II in combination with TMZ in melanomaNCT01605162PARPNiraparibPhase III as monotherapy in breast cancer and as maintenance monotherapy in ovarian cancerNCT01847274; NCT01905592PARPOlaparibOlaparib licensed for use. Olaparib Phase IV as maintenance monotherapy NCT0247696.NCT02476968PARPOlaparibPhase III as monotherapy, maintenance monotherapy and in combination with chemotherapy or cediranib in multiple tumor types (ovarian, breast, gastric, pancreatic)NCT01844986; NCT01874353; NCT01924533; NCT02000622; NCT02032823; NCT02184195; NCT02282020; NCT02392676; NCT02446600; NCT02477644; NCT02502266PARPOlaparibPhase I in combination with RTx (or RTx plus chemotherapy) in various tumor typesNCT01460888; NCT01562210; NCT01758731; NCT02308072; NCT02227082; NCT02229656PARPOlaparibPhase I in combination with AZD1775 in refractory solid tumorsNCT02511795PARPRucaparibPhase III as maintenance monotherapy in ovarian cancerNCT01968213PARPTalazoparibPhase III as monotherapy in metastatic breast cancerNCT01945775PARPVeliparibPhase III in combination with chemotherapy in multiple tumor typesNCT02032277; NCT02106546; NCT02152982; NCT02163694; NCT02264990; NCT02470585PARPVeliparibPhase I and II in combination with RTx (or RTx plus chemotherapy) in various tumor typesNCT01264432; NCT01477489; NCT01514201; NCT01618357; NCT01908478; NCT02412371NHEJDNA-PKcsCC-115Phase I as monotherapy in ASTsNCT01353625DNA-PKcsMSC2490484APhase I as monotherapy or in combination with RTx in ASTs and CLLNCT02316197; NCT02516813HRRATRAZD6738Phase I as monotherapy or in combination with RTx, cytotoxic chemotherapy or olaparib in various tumor typesNCT01955668; NCT02223923; NCT02264678ATRVX-970Phase II in combination with topotecan or cytotoxic chemotherapy in various tumor typesNCT02567409; NCT02487095ATRVX-970Phase I in combination with RTx and cisplatin in HNSCCNCT02567422Checkpoint inhibitorsATMAZD0156Phase I as monotherapy or in combination with cytotoxic chemotherapy, olaparib or novel anti-cancer therapies in advanced tumorsNCT02588105ATR (see above)CHK1GDC-0575Phase I as monotherapy and in combination with cytotoxic chemotherapy in ASTs or lymphomaNCT01564251CHK1MK-8776Phase II in combination with cytarabine in myeloid leukemiaNCT01870596CHK1 and CHK2LY2606368Phase II as monotherapy in breast and ovarian cancerNCT02203513WEE1AZD1775Phase II as monotherapy and in combination with chemotherapy or olaparib in multiple tumor typesNCT01164995; NCT01357161; NCT01827384; NCT02037230; NCT02087176; NCT02087241; NCT02095132; NCT02101775; NCT02196168; NCT02272790; NCT02448329; NCT02513563; NCT02576444WEE1AZD1775Phase I in combination with RTx and TMZ in GBMNCT01849146WEE1AZD1775Phase I in combination with olaparib in refractory solid tumorsNCT02511795Topoisomerase inhibitorsTopo IBelotecanLicensed for useTopo ICRLX101Phase II as monotherapy and in combination with RT, cytotoxic chemotherapy or bevacizumab in various tumor typesNCT00333502; NCT01380769; NCT01652079; NCT01803269; NCT02010567; NCT02187302Topo IIrinotecanLicensed for useTopo ILMP 400Phase I as monotherapy in ASTs and lymphomasNCT01051635; NCT01794104Topo ILMP 776Phase I as monotherapy in ASTs and lymphomasNCT01051635Topo INKTR-102Phase III as monotherapy in locally recurrent or metastatic breast cancerNCT01492101Topo ITopotecanLicensed for useTopo IIDoxorubicinLicensed for useTopo IIEpirubicinLicensed for useTopo IIEtoposideLicensed for useTopo IIIdarubicinLicensed for useTopo IIMitoxantroneLicensed for useTopo IITeniposideLicensed for useAPE1, AP endonuclease 1; AST, advanced solid tumors; ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia and Rad3-related; BER, base excision repair; CLL, chronic lymphocytic leukemia; DDR, DNA damage response; GBM, glioblastoma multiforme; HNSCC, head and neck squamous cell carcinoma; HRR, homologous recombination repair; NHEJ, non-homologous end-joining; NSCLC, non-small-cell lung cancer; PARP, poly(ADP-ribose) polymerase; RTx, radiation therapy; TMZ, temozolomide; Topo, topoisomerase. Open table in a new tab APE1, AP endonuclease 1; AST, advanced solid tumors; ATM, ataxia-telangiectasia mutated; ATR, ataxia-telangiectasia and Rad3-related; BER, base excision repair; CLL, chronic lymphocytic leukemia; DDR, DNA damage response; GBM, glioblastoma multiforme; HNSCC, head and neck squamous cell carcinoma; HRR, homologous recombination repair; NHEJ, non-homologous end-joining; NSCLC, non-small-cell lung cancer; PARP, poly(ADP-ribose) polymerase; RTx, radiation therapy; TMZ, temozolomide; Topo, topoisomerase. Probably the best-known disease-associated examples of defective components of HRR are the breast- and ovarian-associated tumor suppressor genes BRCA1 and BRCA2 (Miki et al., 1994Miki Y. Swensen J. Shattuck-Eidens D. Futreal P.A. Harshman K. Tavtigian S. Liu Q. Cochran C. Bennett L.M. Ding W. et al.A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.Science. 1994; 266: 66-71Crossref PubMed Google Scholar, Wooster et al., 1995Wooster R. Bignell G. Lancaster J. Swift S. Seal S. Mangion J. Collins N. Gregory S. Gumbs C. Micklem G. Identification of the breast cancer susceptibility gene BRCA2.Nature. 1995; 378: 789-792Crossref PubMed Scopus (2165) Google Scholar). Both BRCA1 and BRCA2 proteins are critical for the repair of DSBs by HRR (Prakash et al., 2015Prakash R. Zhang Y. Feng W. Jasin M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins.Cold Spring Harb. Perspect. Biol. 2015; 7: a016600Crossref Scopus (5) Google Scholar), and loss of function results in increased mutation and genome instability (Venkitaraman, 2014Venkitaraman A.R. Cancer suppression by the chromosome custodians, BRCA1 and BRCA2.Science. 2014; 343: 1470-1475Crossref PubMed Scopus (17) Google Scholar). It is this increased genomic instability that is thought to be responsible for the significantly increased cancer risk of patients with familial or germline BRCA (gBRCA) mutations. However, the lack of functional BRCA1 or BRCA2 in tumors also represents an opportunity for targeted treatment with PARP inhibitors. Published data in 2005 (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 (1441) Google Scholar, Farmer et al., 2005Farmer H. McCabe N. Lord C.J. Tutt A.N. 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 (1885) Google Scholar) demonstrated the potential for PARP inhibitors to induce cell death in BRCA-deficient cells through the concept of synthetic lethality. In Farmer et al., 2005Farmer H. McCabe N. Lord C.J. Tutt A.N. 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 (1885) Google Scholar, the differential PARP inhibitor activity seen between BRCA homozygous mutant (BRCA1−/−) cells and BRCA heterozygous (BRCA1−/+) and wild-type (BRCA1+/+) cells was approximately 1,000-fold. PARP inhibition in BRCA-deficient cancers was therefore predicted to have significantly reduced effects on normal cells that were wild-type or heterozygous for BRCA1 or BR
Referência(s)