PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells
2019; Elsevier BV; Volume: 29; Issue: 10 Linguagem: Inglês
10.1016/j.tcb.2019.07.008
ISSN1879-3088
AutoresSylvie M. Noordermeer, Haico van Attikum,
Tópico(s)CRISPR and Genetic Engineering
ResumoHomologous recombination (HR)-deficient tumors are hypersensitive to poly-(ADP)-ribose polymerase inhibitors (PARPi)-induced DNA damage. Therefore, PARPi have shown great promise in the clinic, but rates of pre-existing and acquired resistance are high.Four main mechanisms of PARPi resistance have been characterized, representing those that impact on (i) cellular availability of the inhibitor, (ii) the activity and abundance of PAR chains, (iii) reactivation of HR, and (iv) replication fork protection.Loss of the 53BP1–RIF1–REV7–Shieldin axis, that is involved in non-homologous end-joining repair of DNA double-strand breaks, reactivates resection and HR in BRCA1-deficient cells, leading to PARPi resistance. Shieldin seems to shield broken ends by blocking access to nucleases. The exact mechanism by which Shieldin controls resection needs to be resolved.Studies in large patient cohorts will need to clarify the clinical relevance of the different PARPi resistance mechanisms. Furthermore, research on resistance mechanisms will drive future genetic screening of resistance factors to guide therapy decisions. Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities. Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities. Genomic instability is one of the enabling characteristics of tumor development [1.Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (24860) Google Scholar]. To maintain genomic integrity, cells are equipped with multiple mechanisms to repair a wide variety of DNA lesions caused by exogenous and endogenous events. One particularly toxic lesion is the DNA double-strand break (DSB; see Glossary). This lesion can be caused by ionizing irradiation and genotoxic chemicals, but can also arise as an intermediate of resolving stalled or collapsed replication forks (replication fork instability) [2.Ait Saada A. et al.Preserving replication fork integrity and competence via the homologous recombination pathway.DNA Repair (Amst). 2018; 71: 135-147Crossref PubMed Scopus (0) Google Scholar]. If left unrepaired or are repaired incorrectly, DSBs can give rise to mutations, deletions, amplifications, and chromosomal translocations, leading to various outcomes such as senescence, cell death, or malignant transformation. Over 30 years ago, Marie-Claire King and colleagues discovered the linkage between familial early-onset breast cancer and the genomic region 17q21 [3.Hall J.M. et al.Linkage of early-onset familial breast cancer to chromosome 17q21.Science. 1990; 250: 1684-1689Crossref PubMed Google Scholar]. We now know that the gene affected is BRCA1, and that mutations in this gene are not only linked to breast cancer but also to familial cases of ovarian cancer and sporadic tumors of different origins [4.Kandoth C. et al.Mutational landscape and significance across 12 major cancer types.Nature. 2013; 502: 333-339Crossref PubMed Scopus (1721) Google Scholar, 5.Martincorena I. Campbell P.J. Somatic mutation in cancer and normal cells.Science. 2015; 349: 1483-1489Crossref PubMed Scopus (255) Google Scholar, 6.Konstantinopoulos P.A. et al.Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer.Cancer Discov. 2015; 5: 1137-1154Crossref PubMed Scopus (169) Google Scholar, 7.Turner N.C. Signatures of DNA-repair deficiencies in breast cancer.N. Engl. J. Med. 2017; 377: 2490-2492Crossref PubMed Scopus (4) Google Scholar]. BRCA1 is an essential factor in the repair of DSBs via homologous recombination (HR) (see Box 1 for a more detailed overview of DSB repair). Moreover, homozygous loss of BRCA1 is not tolerated during human and mouse embryonic development [8.Evers B. Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects.Oncogene. 2006; 25: 5885-5897Crossref PubMed Scopus (138) Google Scholar]. This BRCA1 survival-dependency can be partially overcome by concomitant loss of p53 [9.Hakem R. et al.Partial rescue of Brca1 (5–6) early embryonic lethality by p53 or p21 null mutation.Nat. Genet. 1997; 16: 298-302Crossref PubMed Scopus (0) Google Scholar]. Importantly, mouse models with mammary gland-specific loss of these genes show increased breast tumor formation [8.Evers B. Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects.Oncogene. 2006; 25: 5885-5897Crossref PubMed Scopus (138) Google Scholar]. Indeed, in clinical tumor samples, BRCA1 mutations often co-occur – but not always – with TP53 mutations [8.Evers B. Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects.Oncogene. 2006; 25: 5885-5897Crossref PubMed Scopus (138) Google Scholar, 10.Kringen P. et al.TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival.BMC Cancer. 2005; 5: 134Crossref PubMed Scopus (16) Google Scholar]. Epigenetic silencing of BRCA1 expression via promoter hypermethylation is another way of reducing BRCA1 activity, and this has been shown to occur frequently in tumors [6.Konstantinopoulos P.A. et al.Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer.Cancer Discov. 2015; 5: 1137-1154Crossref PubMed Scopus (169) Google Scholar, 11.Shakeri H. et al.Methylation analysis of BRCA1 and APC in breast cancer and its relationship to clinicopathological features.Clin. Lab. 2016; 62: 2333-2337Crossref PubMed Scopus (5) Google Scholar, 12.Vos S. et al.BRCA promoter methylation in sporadic versus BRCA germline mutation-related breast cancers.Breast Cancer Res. 2017; 19: 64Crossref PubMed Scopus (0) Google Scholar]. In addition to aberrations in BRCA1, genes encoding many more factors involved in HR, such as BRCA2, PALB2, and RAD51, are known to be affected in a wide variety of tumors. All these tumors display severe chromosomal instability as a result of deregulated HR, a phenotype referred to as 'BRCAness' [13.Lord C.J. Ashworth A. BRCAness revisited.Nat. Rev. Cancer. 2016; 16: 110-120Crossref PubMed Scopus (287) Google Scholar].Box 1DNA Double-Strand Break RepairDSBs are the most cytotoxic DNA lesions because they cause full disruption of a chromosome. If left unrepaired or repaired incorrectly, DSBs can lead to chromosomal deletions, insertions, duplications, and translocations. Cells are equipped with various mechanisms to repair DSBs (Figure I): homologous recombination (HR), canonical NHEJ (cNHEJ), alternative end joining (a-EJ), and single-strand annealing (SSA).In mammalian cells, cNHEJ is the most frequent type of repair [108.Mladenov E. Iliakis G. Induction and repair of DNA double strand breaks: the increasing spectrum of non-homologous end joining pathways.Mutat. Res. 2011; 711: 61-72Crossref PubMed Scopus (247) Google Scholar]. The broken ends are bound by KU70/80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming the DNA-PK complex, which recruits the ligation machinery of XRCC4, ligase IV, and XLF. This type of repair requires no or minimal end-processing, potentially leading to small insertions or deletions. cNHEJ plays an important role in immune receptor diversification because both V(D)J recombination and class-switch recombination (CSR) are mediated via cNHEJ. In addition to the core factors mentioned above, 53BP1 and its downstream factors RIF1, REV7, and the Shieldin complex are required for efficient cNHEJ (see Box 2 for more information).In S and G2, when DNA replication occurs and a sister chromatid is present, repair can occur via HR (Figure I). Upon extensive end-resection of the break by endo- and exonucleases such as MRE11, CtIP, DNA2, and EXO1, yielding 3′ single-stranded (ss)DNA overhangs, this ssDNA stretch forms filaments with RPA. Subsequently, RPA is replaced by RAD51 with the help of the BRCA2–PALB2 complex [109.Yuan S.S. et al.BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo.Cancer Res. 1999; 59: 3547-3551PubMed Google Scholar]. RAD51 invades the homologous sequence present in the sister chromatid and uses it as a template for DNA synthesis and accurate repair. BRCA1 has several functions in HR, ranging from activating resection to enhancing RAD51 recombinase activity [54.Bunting S.F. et al.53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.Cell. 2010; 141: 243-254Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar, 55.Bouwman P. et al.53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.Nat. Struct. Mol. Biol. 2010; 17: 688-695Crossref PubMed Scopus (520) Google Scholar, 110.Zhao W. et al.BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing.Nature. 2017; 550: 360-365Crossref PubMed Scopus (0) Google Scholar].When cNHEJ or HR are compromised or unavailable, the cell employs error-prone a-EJ and SSA mechanisms for repair. Repair via a-EJ requires some extent of resection, is characterized by the use of microhomology [111.Roerink S.F. et al.Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans.Genome Res. 2014; 24: 954-962Crossref PubMed Scopus (58) Google Scholar], and is dependent on LIG3 and POLQ. Loss of a-EJ is synthetic lethal with HR deficiency, suggesting that it functions as a backup mechanism for HR [112.Ceccaldi R. et al.Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair.Nature. 2015; 518: 258-262Crossref PubMed Scopus (213) Google Scholar, 113.Mateos-Gomez P.A. et al.Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination.Nature. 2015; 518: 254-257Crossref PubMed Scopus (190) Google Scholar]. SSA requires larger stretches of resection and is dependent on ERCC1 and RAD52 [114.Bhargava R. et al.Regulation of single-strand annealing and its role in genome maintenance.Trends Genet. 2016; 32: 566-575Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar] (Figure I).DSB pathway choice is tightly regulated throughout the cell cycle by several mechanisms that restrict HR activity to S/G2 phase. A CDK-specific phosphorylation event on T847 of CtIP in S/G2 enables its resection activity in these cell-cycle phases [115.Huertas P. Jackson S.P. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair.J. Biol. Chem. 2009; 284: 9558-9565Crossref PubMed Scopus (259) Google Scholar]. In addition, recruitment of BRCA1 to DSBs [57.Escribano-Diaz C. 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 (0) Google Scholar, 63.Feng L. et al.RIF1 counteracts BRCA1-mediated end resection during DNA repair.J. Biol. Chem. 2013; 288: 11135-11143Crossref PubMed Scopus (147) Google Scholar], as well as its interaction with PALB2 [116.Orthwein A. et al.A mechanism for the suppression of homologous recombination in G1 cells.Nature. 2015; 528: 422-426Crossref PubMed Google Scholar] – both necessary for HR activity – are inhibited during G1. BRCA1 recruitment to S/G2-specific DSBs is mediated via binding of its partner BARD1 to unmethylated H4K20 present on new histones in post-replicative chromatin [117.Nakamura K. et al.H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids.Nat. Cell Biol. 2019; 21: 311-318Crossref PubMed Scopus (0) Google Scholar]. Furthermore, BRCA1 association with S/G2 phase-specific breaks seems to exclude 53BP1 and RIF1 association, thereby preventing NHEJ [118.Chapman J.R. et al.BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair.J. Cell Sci. 2012; 125: 3529-3534Crossref PubMed Scopus (141) Google Scholar, 119.Densham R.M. et al.Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection.Nat. Struct. Mol. Biol. 2016; 23: 647-655Crossref PubMed Google Scholar]. Another mechanism to inhibit NHEJ in S/G2 is mediated by the KU-binding protein cyren, which inhibits NHEJ by binding and protecting breaks with overhangs [120.Arnoult N. et al.Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN.Nature. 2017; 549: 548-552Crossref PubMed Scopus (9) Google Scholar]. All these mechanisms ensure that HR activation only takes place when a sister chromatid template is available. Remarkably, it has been shown that, even in G2, only 15–20% of DSBs are repaired via HR [121.Beucher A. et al.ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2.EMBO J. 2009; 28: 3413-3427Crossref PubMed Scopus (291) Google Scholar]. This indicates that other cell cycle-independent aspects may play a role in pathway choice, such as chromatin context and break complexity [122.Shibata A. et al.Factors determining DNA double-strand break repair pathway choice in G2 phase.EMBO J. 2011; 30: 1079-1092Crossref PubMed Scopus (256) Google Scholar]. DSBs are the most cytotoxic DNA lesions because they cause full disruption of a chromosome. If left unrepaired or repaired incorrectly, DSBs can lead to chromosomal deletions, insertions, duplications, and translocations. Cells are equipped with various mechanisms to repair DSBs (Figure I): homologous recombination (HR), canonical NHEJ (cNHEJ), alternative end joining (a-EJ), and single-strand annealing (SSA). In mammalian cells, cNHEJ is the most frequent type of repair [108.Mladenov E. Iliakis G. Induction and repair of DNA double strand breaks: the increasing spectrum of non-homologous end joining pathways.Mutat. Res. 2011; 711: 61-72Crossref PubMed Scopus (247) Google Scholar]. The broken ends are bound by KU70/80 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs), forming the DNA-PK complex, which recruits the ligation machinery of XRCC4, ligase IV, and XLF. This type of repair requires no or minimal end-processing, potentially leading to small insertions or deletions. cNHEJ plays an important role in immune receptor diversification because both V(D)J recombination and class-switch recombination (CSR) are mediated via cNHEJ. In addition to the core factors mentioned above, 53BP1 and its downstream factors RIF1, REV7, and the Shieldin complex are required for efficient cNHEJ (see Box 2 for more information). In S and G2, when DNA replication occurs and a sister chromatid is present, repair can occur via HR (Figure I). Upon extensive end-resection of the break by endo- and exonucleases such as MRE11, CtIP, DNA2, and EXO1, yielding 3′ single-stranded (ss)DNA overhangs, this ssDNA stretch forms filaments with RPA. Subsequently, RPA is replaced by RAD51 with the help of the BRCA2–PALB2 complex [109.Yuan S.S. et al.BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo.Cancer Res. 1999; 59: 3547-3551PubMed Google Scholar]. RAD51 invades the homologous sequence present in the sister chromatid and uses it as a template for DNA synthesis and accurate repair. BRCA1 has several functions in HR, ranging from activating resection to enhancing RAD51 recombinase activity [54.Bunting S.F. et al.53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.Cell. 2010; 141: 243-254Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar, 55.Bouwman P. et al.53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.Nat. Struct. Mol. Biol. 2010; 17: 688-695Crossref PubMed Scopus (520) Google Scholar, 110.Zhao W. et al.BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing.Nature. 2017; 550: 360-365Crossref PubMed Scopus (0) Google Scholar]. When cNHEJ or HR are compromised or unavailable, the cell employs error-prone a-EJ and SSA mechanisms for repair. Repair via a-EJ requires some extent of resection, is characterized by the use of microhomology [111.Roerink S.F. et al.Polymerase theta-mediated end joining of replication-associated DNA breaks in C. elegans.Genome Res. 2014; 24: 954-962Crossref PubMed Scopus (58) Google Scholar], and is dependent on LIG3 and POLQ. Loss of a-EJ is synthetic lethal with HR deficiency, suggesting that it functions as a backup mechanism for HR [112.Ceccaldi R. et al.Homologous-recombination-deficient tumours are dependent on Poltheta-mediated repair.Nature. 2015; 518: 258-262Crossref PubMed Scopus (213) Google Scholar, 113.Mateos-Gomez P.A. et al.Mammalian polymerase theta promotes alternative NHEJ and suppresses recombination.Nature. 2015; 518: 254-257Crossref PubMed Scopus (190) Google Scholar]. SSA requires larger stretches of resection and is dependent on ERCC1 and RAD52 [114.Bhargava R. et al.Regulation of single-strand annealing and its role in genome maintenance.Trends Genet. 2016; 32: 566-575Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar] (Figure I). DSB pathway choice is tightly regulated throughout the cell cycle by several mechanisms that restrict HR activity to S/G2 phase. A CDK-specific phosphorylation event on T847 of CtIP in S/G2 enables its resection activity in these cell-cycle phases [115.Huertas P. Jackson S.P. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair.J. Biol. Chem. 2009; 284: 9558-9565Crossref PubMed Scopus (259) Google Scholar]. In addition, recruitment of BRCA1 to DSBs [57.Escribano-Diaz C. 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 (0) Google Scholar, 63.Feng L. et al.RIF1 counteracts BRCA1-mediated end resection during DNA repair.J. Biol. Chem. 2013; 288: 11135-11143Crossref PubMed Scopus (147) Google Scholar], as well as its interaction with PALB2 [116.Orthwein A. et al.A mechanism for the suppression of homologous recombination in G1 cells.Nature. 2015; 528: 422-426Crossref PubMed Google Scholar] – both necessary for HR activity – are inhibited during G1. BRCA1 recruitment to S/G2-specific DSBs is mediated via binding of its partner BARD1 to unmethylated H4K20 present on new histones in post-replicative chromatin [117.Nakamura K. et al.H4K20me0 recognition by BRCA1–BARD1 directs homologous recombination to sister chromatids.Nat. Cell Biol. 2019; 21: 311-318Crossref PubMed Scopus (0) Google Scholar]. Furthermore, BRCA1 association with S/G2 phase-specific breaks seems to exclude 53BP1 and RIF1 association, thereby preventing NHEJ [118.Chapman J.R. et al.BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair.J. Cell Sci. 2012; 125: 3529-3534Crossref PubMed Scopus (141) Google Scholar, 119.Densham R.M. et al.Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection.Nat. Struct. Mol. Biol. 2016; 23: 647-655Crossref PubMed Google Scholar]. Another mechanism to inhibit NHEJ in S/G2 is mediated by the KU-binding protein cyren, which inhibits NHEJ by binding and protecting breaks with overhangs [120.Arnoult N. et al.Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN.Nature. 2017; 549: 548-552Crossref PubMed Scopus (9) Google Scholar]. All these mechanisms ensure that HR activation only takes place when a sister chromatid template is available. Remarkably, it has been shown that, even in G2, only 15–20% of DSBs are repaired via HR [121.Beucher A. et al.ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2.EMBO J. 2009; 28: 3413-3427Crossref PubMed Scopus (291) Google Scholar]. This indicates that other cell cycle-independent aspects may play a role in pathway choice, such as chromatin context and break complexity [122.Shibata A. et al.Factors determining DNA double-strand break repair pathway choice in G2 phase.EMBO J. 2011; 30: 1079-1092Crossref PubMed Scopus (256) Google Scholar]. The increased chromosomal instability of HR-deficient tumors renders these cells highly sensitive to DNA damaging drugs such as platinum compounds, which have been the standard of care for ovarian tumors for many decades. In 2005, Bryant et al. and Farmer et al. first described the synthetic lethal interaction of PARP inhibition with HR deficiency as a promising new approach for the targeted treatment of BRCA1/2-deficient tumors [14.Bryant H.E. et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.Nature. 2005; 434: 913-917Crossref PubMed Scopus (2450) Google Scholar, 15.Farmer H. et al.Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.Nature. 2005; 434: 917-921Crossref PubMed Scopus (3206) Google Scholar]. The family of PARP proteins mediates post-translational PARylation of substrate proteins involved in processes such as transcription and DNA damage repair. PARP1 is a particularly important protein for sensing single-stranded (ss)DNA breaks (SSBs), and recent data have shown that unligated Okazaki fragments are the trigger for PARP activation during replication in unperturbed S-phase cells [16.Hanzlikova H. et al.The importance of poly(ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication.Mol. Cell. 2018; 71 (e313): 319-331Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. PARPi not only block the activity of PARP1 for the repair of these lesions but also trap the protein on the damaged DNA (Figure 1). Such structures add to the cytotoxic effect of these drugs by posing an insurmountable block to the replisome [17.Murai J. et al.Trapping of PARP1 and PARP2 by clinical PARP inhibitors.Cancer Res. 2012; 72: 5588-5599Crossref PubMed Scopus (622) Google Scholar, 18.Murai J. et al.Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib.Mol. Cancer Ther. 2014; 13: 433-443Crossref PubMed Scopus (232) Google Scholar]. Cells require functional HR to resolve these blocks and resume cell-cycle progression, and PARPi hence induce cell death in HR-deficient tumors. The first clinical trials to explore synthetic lethality using PARPi as a treatment for platinum-sensitive BRCA1/2-mutated breast and ovarian tumors showed great promise [19.Fong P.C. et al.Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N. Engl. J. Med. 2009; 361: 123-134Crossref PubMed Scopus (2335) Google Scholar, 20.Mirza M.R. et al.Latest clinical evidence and further development of PARP inhibitors in ovarian cancer.Ann. Oncol. 2018; 29: 1366-1376Crossref PubMed Scopus (4) Google Scholar]. Since 2014, several PARPi have been FDA- and/or EMA-approved as monotherapy or combination therapy for BRCA-mutated and/or platinum-sensitive breast and ovarian tumors (reviewed in [21.Gourley C. et al.Moving from poly(ADP-ribose) polymerase inhibition to targeting DNA repair and DNA damage response in cancer therapy.J. Clin. Oncol. 2019; (Published online 13 May 2019. http://doi.org/10.1200/JCO.18.02050)Crossref Google Scholar]). Recently, a Phase Ib trial has shown encouraging results using the synthetic lethal interaction between PARP inhibition and HR deficiency by simultaneous chemical inhibition of PARP and HR in cells genetically proficient for HR [22.Konstantinopoulos P.A. et al.Olaparib and alpha-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial.Lancet Oncol. 2019; 20: 570-580Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Such chemically induced synthetic lethal approaches open the possibility of treating many types of cancer that are either deficient or proficient for HR. Studies in patients as well as in mouse models have shown that response rates to PARPi are often marred by high rates of resistance [19.Fong P.C. et al.Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.N. Engl. J. Med. 2009; 361: 123-134Crossref PubMed Scopus (2335) Google Scholar, 23.Rottenberg S. et al.High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 17079-17084Crossref PubMed Scopus (548) Google Scholar]. Importantly, resistance to platinum-based chemotherapies is a strong predictor for PARPi resistance, indicating they probably share common mechanisms [24.Fong P.C. et al.Poly(ADP-ribose) polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.J. Clin. Oncol. 2010; 28: 2512-2519Crossref PubMed Scopus (0) Google Scholar]. As a result of extensive in vivo and in vitro studies, several resistance mechanisms have been identified. These mechanisms can be classified into four main categories representing those that (i) influence cellular availability of the inhibitor, (ii) directly impact on the activity and abundance of PAR chains, (iii) lead to reactivation of HR, and (iv) influence replication fork protection (Figure 2). In this review we give an overview of current knowledge about the mechanisms of PARPi resistance in HR-deficient cells, and we discuss how this knowledge has improved our understanding of DNA damage repair. In a murine model of Brca1-deficient breast tumors, the majority of tumors that displayed resistance to PARPi showed overexpression of drug-efflux transporter genes (Abcb1a and Abcb1b encoding for MDR1/P-gp, and Abcg2) [23.Rottenberg S. et al.High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 17079-17084Crossref PubMed Scopus (548) Google Scholar]. Mouse models of mesenchymal carcinosarcomas characterized by epithelial-to-mesenchymal transition phenotypes showed especially high rates of PARPi resistance accompanied by high expression of Abcb1a/b [25.Jaspers J.E. et al.BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.Cancer Res. 2015; 75: 732-741Crossref PubMed Scopus (18) Google Scholar]. Importantly, overexpression of Abcb1a/b was also found to be a common cause of resistance to topoisomerase I and II inhibitors (topotecan and doxorubicin, respectively) in mouse mammary tumors [25.Jaspers J.E. et al.BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.Cancer Res. 2015; 75: 732-741Crossref PubMed Scopus (18) Google Scholar, 26.Rottenberg S. et al.Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 12117-12122Crossref PubMed Scopus (0) Google Scholar]. Consequently, coadministration of the MDR1 inhibitor tariquidar resensitized the tumors to the topoisomerase inhibitors [25.Jaspers J.E. et al.BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.Cancer Res. 2015; 75: 732-741Crossref PubMed Scopus (18) Google Scholar] and PARPi [23.Rottenberg S. et al.High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs.Proc. Natl. Acad. Sci. U. S. A. 2008; 105: 17079-17084Crossref PubMed Scopus (548) Google Scholar]. Overexpression of ABCB1 has also been observed in a PARPi-resistant human ovarian cancer cell line, and resistance could be reversed by cotreatment with the MDR1 inhibitors verapamil and elacridar [27.Vaidyanathan A. et al.ABCB1 (MDR1) induction defines a common resistance mechanism in paclitaxel- and olaparib-resistant ovarian cancer cells.Br. J. Cancer. 2016; 115: 431-441Crossref PubMed Scopus (16) Google Scholar]. Furthermore, recent evidence suggests that ABCB1 expression is often upregulated in chemotherapy-treated ovarian and breast cancers as a result of chromosomal translocations involving the gene [28.Christie E.L. et al.Multiple ABCB1 transcriptional fusions in drug resistant high-grade serous ovarian and breast cancer.Nat. Commun. 2019; 10: 1295Crossref PubMed Scopus (0) Google Scholar].
Referência(s)