The discovery of the first poly(ADP-ribose) polymerase (PARP) was made over 50 years ago in Paul Mandel’s laboratory, with the observation of the synthesis of a new polyadenylic acid after nicotinamide mononucleotide had been added to rat liver extracts. By 1980 it was known that this nuclear enzyme was activated by DNA damage and played an essential role in the repair of DNA.[2-4] There are now 17 known members of the PARP nuclear superfamily, with PARP1 and PARP2 as the two that are predominantly involved in DNA repair.
It was discovered that in cancer cells in which repair of DNA is already impaired, inhibition of PARP, by increasing genomic instability, can result in the death of the tumor cells. The antitumor effects of PARP inhibition were first demonstrated in ovarian cancer cells.[3,4,7,8] Olaparib was the first PARP inhibitor to be approved by the US Food and Drug Administration (FDA); it was granted accelerated approval for use in BRCA1/2 mutation carriers in the fourth or greater treatment line, based on clinical data reporting antitumor activity that resulted in significant clinical benefit in high-grade serous ovarian cancer (HGSOC) with germline mutations in the BRCA1 or BRCA2 gene. Olaparib is approved in Europe for women with either germline or somatic deleterious mutations for maintenance of chemotherapy response to second- or later-line platinum-based therapy, after completion of the last platinum regimen. Olaparib has also been approved by Health Canada.
Ongoing phase II and III clinical trials are testing the efficacy of currently available PARP inhibitors—olaparib, niraparib, rucaparib, veliparib, and talazoparib—that have also shown antitumor efficacy and tolerability alone or when adding a synergistic effect in combination with other agents (Table 1). Rucaparib just received FDA approval in December 2016 for use in women with HGSOC in the third or greater line, especially patients with homologous recombination (HR) dysfunction as shown by an HR dysfunction companion diagnostic. Niraparib activity in maintenance of chemotherapy response in patients with recurrent ovarian cancer was reported in November 2016 and is awaiting review by the FDA and the European Medicines Agency (EMA).
DNA Repair and the Role of PARP
Two major forms of DNA damage can occur: single-strand breaks (SSBs) and double-strand breaks (DSBs). Thus, there are two repair pathway categories: SSB-targeted and DSB-targeted repair pathways. Base excision repair (BER) is one of several pathways involved in the repair of selected types of DNA SSBs. PARP1, via a process known as PARylation (poly[ADP-ribose] polymerization), plays an important role in the BER of DNA SSBs. In the nucleus, PARP1 senses SSB DNA injury and recruits DNA repair complexes to the site of SSBs (Figure 1).
If PARylation is inhibited and BER is impaired, unrepaired or misrepaired SSBs accumulate, and at replication forks they degenerate to become DSBs. DSBs are repaired predominantly by the high-fidelity HR repair pathway that is active in the G2 phase of the cell cycle. The low-fidelity nonhomologous end-joining (NHEJ) program, which functions predominantly in the G1/S transition and S phase, is a poor-quality DSB repair backup; this form of repair religates DNA strands indiscriminately, introducing new DNA errors that cumulatively can result in cell death. (Figure 2).
BRCA1 and BRCA2 are tumor suppressor genes known for the association of their deleterious germline mutations with familial, high-penetrance breast and ovarian cancers. Both BRCA1 and BRCA2 are involved in HR repair of DSBs and help maintain genomic stability. Cells with homozygous loss of normal BRCA1/2 function have defective HR and must rely more on the low-fidelity NHEJ program to repair DNA DSBs. Thus, cells with deleterious mutations in BRCA1 or BRCA2 are more dependent on BER and PARP1 for rescue and maintenance of genomic stability—and consequently more susceptible to impairment of the BER pathway. In such cells, PARP inhibition results in further genomic instability and cell death.
In addition to tumors with deleterious germline BRCA1 (gBRCA1) or gBRCA2 mutations, other tumors in which HR is dysfunctional, such as those in which HR dysfunction results from genomic events besides germline mutations—eg, homozygous loss by somatic mutation, silencing by methylation, or loss of other HR proteins, such as RAD51c—are also more susceptible to PARP inhibition. In such settings, a program of clinical “synthetic lethality” is activated. Synthetic lethality exists when two conditions that independently would not cause cell death are applied in combination and together cause lethal injury.[12,13] Cancer cells already have impaired DNA repair function and a higher burden of genomic injury than normal cells; in tumors in which there has also been genomic loss of DNA repair function or other impairment of HR, synthetic lethality, as induced by PARP inhibition, may be used to target tumor tissue selectively, with decreased toxicity in normal cells that have intact repair pathways and thus are more able to survive an onslaught of DNA repair inhibitors.[14,15]
Development of PARP Inhibitors as Viable Anticancer Agents
The finding that PARP inhibitors were at least additive with platinums and other agents and resulted in clinical synthetic lethality when applied to HR-deficient cells led to the development of several NAD-mimetic PARP inhibitors. It is unclear which of these agents’ many mechanisms of action are primary to their clinical activity. PARP inhibitors block the PARylation that normally occurs in response to DNA damage. All PARP inhibitors have the capacity to trap the PARP enzyme on injured DNA, preventing binding of incoming repair proteins. Both the binding and dissociation affinities are critical, as the longer the PARP enzyme is trapped on DNA (a result of higher affinity), the greater the benefit observed in preclinical models. The other major role of PARP inhibition is regulation of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), the rate-limiting enzyme involved in NHEJ. PARP1 keeps DNA-PKcs in an inactive mode, inhibiting NHEJ activity. Upon loss of PARP1, DNA-PKcs is phosphorylated and activated, thereby promoting the dysfunctional and injurious DSB repair performed by the NHEJ program.
1. Chambon P, Weill JD, Mandel P. Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme. Biochem Biophys Res Commun. 1963;11:39-43.
2. Benjamin RC, Gill DM. ADP-ribosylation in mammalian cell ghosts. Dependence of poly(ADP-ribose) synthesis on strand breakage in DNA. J Biol Chem. 1980;255:10493-501.
3. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913-7.
4. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-21.
5. Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10:293-301.
6. Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10:293-301.
7. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72:1117-30.
8. King MC, Marks JH, Mandell JB. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643-6.
9. Morgan MA, Parsels LA, Maybaum J, Lawrence TS. Improving the efficacy of chemoradiation with targeted agents. Cancer Discov. 2014;4:280-91.
10. Clamp A, Jayson G. PARP inhibitors in BRCA mutation-associated ovarian cancer. Lancet Oncol. 2015;16:10-2.
11. Drew Y. The development of PARP inhibitors in ovarian cancer: from bench to bedside. Br J Cancer. 2015;113(suppl 1):S3-S9.
12. Kaelin WG Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5:689-98.
13. McLornan DP, List A, Mufti GJ. Applying synthetic lethality for the selective targeting of cancer. N Engl J Med. 2014;371:1725-35.
14. Bryant H E, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434:913-7.
15. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917-21.
16. Zha S, Jiang W, Fujiwara Y, et al. Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. Proc Natl Acad Sci USA. 2011;108:2028-33.
17. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366:1382-92.
18. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33:244-50.
19. Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.J Clin Oncol. 2010;28:2512-9.
20. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15:852-61.
21. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-44.
22. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443-53.
23. Gallagher DJ, Gaudet MM, Pal P, et al. Germline BRCA mutations denote a clinicopathologic subset of prostate cancer. Clin Cancer Res. 2010;16:2115-21.
24. Kote-Jarai Z, Leongamornlert D, Saunders E, et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011;105:1230-4.
25. Leongamornlert D, Saunders E, Dadaev T, et al. Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. Br J Cancer. 2014;110:1663-72.
26. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697-708.
27. Bang YJ, Im SA, Lee KW, et al. Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol. 2015;33:3858-65.
28. Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14:882-92.
29. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375:2154-64.
30. Jones P, Wilcoxen K, Rowley M, Toniatti C. Niraparib: a poly(ADP-ribose) polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination. J Med Chem. 2015;58:3302-14.
31. Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14:882-92.
32. Plummer R, Jones C, Middleton M, et al. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin Cancer Res. 2008;14:7917-23.
33. Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18:75-87.
34. Donawho CK, Luo Y, Luo Y, et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007;13:2728-37.
35. Kummar S, Oza AM, Fleming GF, et al. Randomized trial of oral cyclophosphamide and veliparib in high-grade serous ovarian, primary peritoneal, or fallopian tube cancers, or BRCA-mutant ovarian cancer. Clin Cancer Res. 2015;21:1574-82.
36. Coleman RL, Sill MW, Bell-McGuinn K, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation—an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2015;137:386-91.
37. Shen Y, Rehman FL, Feng Y, et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013;19:5003-15.
38. Smith MA, Hampton OA, Reynolds CP, et al. Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673. Pediatr Blood Cancer. 2015;62:91-8.
39. Mukhopadhyay A, Elattar A, Cerbinskaite A, et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Res. 2010;16:2344-51.
40. Ivy SP, Liu JF, Lee JM, et al. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer. Expert Opin Investig Drugs. 2016;25:597-611.
41. Bindra RS, Gibson SL, Meng A, et al. Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res. 2005;65:11597-604.
42. Gibson SL, Bindra RS, Glazer PM. Hypoxia-induced phosphorylation of Chk2 in an ataxia telangiectasia mutated-dependent manner. Cancer Res. 2005;65:10734-41.
43. Chan N, Pires IM, Bencokova Z, et al. Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment. Cancer Res. 2010;70:8045-54.
44. Liu JF, Tolaney SM, Birrer M, et al. A phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. Eur J Cancer. 2013;49:2972-8.
45. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15:1207-14.
46. Liu IH, Ford JM, Kunz PL. DNA-repair defects in pancreatic neuroendocrine tumors and potential clinical applications. Cancer Treat Rev. 2016;44:1-9.
47. Miknyoczki SJ, Jones-Bolin S, Pritchard S, et al. Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol Cancer Ther. 2003;2:371-82.
48. Tentori L, Leonetti C, Scarsella M, et al. Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res. 2003;9:5370-9.
49. Tentori L, Portarena I, Barbarino M, et al. Inhibition of telomerase increases resistance of melanoma cells to temozolomide, but not to temozolomide combined with poly(ADP-ribose) polymerase inhibitor. Mol Pharmacol. 2003;63:192-202.
50. Plummer R, Lorigan P, Steven N, et al. A phase II study of the potent PARP inhibitor, rucaparib (PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating evidence of chemopotentiation. Cancer Chemother Pharmacol. 2013;71:1191-9.