Current researches on PARP inhibitors and its treatment of germline BRCA mutated breast cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LI Shaozhong ,  LIU Jing ,  ZHANG Guojun

Changjiang Scholar’s Laboratory/Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Breast Cancer, Shantou University Medical College, Shantou, Guangdong 515041, P. R. China;

Corresponding author：

LIU Jing, Email: jliu12@stu.edu.cn; ZHANG Guojun, Email: guoj_zhang@yahoo.com

Keywords：

poly ADP-ribose polymerase; susceptibility gene; breast cancer; synergetic death

DOI：

10.7507/1007-9424.201812014

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize functions and mechanisms of poly ADP-ribose polymerase (PARP) inhibitors and its application in germline BRCA mutated breast cancer.Method The literatures about the PARP inhibitors and their applications in the treatment of germline BRCA mutated breast cancer at home and abroad in recent years were collected to make a review.Results As a DNA repair enzyme, the PARP played an important role in the DNA repair pathway. Based on this mechanism, the PARP inhibitors had been developed and widely used in the clinic. On the other hand, the previous studies had shown that the PARP inhibitors marked the synthetic lethal effect in the cancers with homologous recombination deficiency mechanism. By inhibiting the PARP activity in the tumor cells with BRCA mutation, all the DNA damage repair pathways were blocked, which could induce the cell apoptosis or increase the sensitivity of tumor cells to chemoradiotherapy, resulting in the cell death.Conclusion In patients with germline BRCA mutated breast cancer, PARP inhibitors can selectively kill breast cancer cells and show a high potential for individualized treatment.

Citation： LI Shaozhong, LIU Jing, ZHANG Guojun. Current researches on PARP inhibitors and its treatment of germline BRCA mutated breast cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2019, 26(6): 748-752. doi: 10.7507/1007-9424.201812014 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res, 2007, 13(15 Pt 1): 4429-4434.
3.	Curigliano G, Goldhirsch A. The triple-negative subtype: new ideas for the poorest prognosis breast cancer. J Natl Cancer Inst Monogr, 2011, 2011(43): 108-110.
4.	Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med, 2010, 363(20): 1938-1948.
5.	Bayraktar S, Gutierrez-Barrera AM, Liu D, et al. Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations. Breast Cancer Res Treat, 2011, 130(1): 145-153.
6.	King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 2003, 302(5645): 643-646.
7.	Ashworth 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(22): 3785-3790.
8.	李文新. BRCA-1和PARP-1在三阴乳腺癌中表达及意义. 内蒙古医科大学学报, 2017, 39(6): 483-489.
9.	Ohmoto A, Yachida S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther, 2017, 10: 5195-5208.
10.	Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer, 2010, 10(4): 293-301.
11.	Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors? Nat Rev Clin Oncol, 2018, 15(9): 564-576.
12.	Nijman SM. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett, 2011, 585(1): 1-6.
13.	Langelier MF, Planck JL, Roy S, et al. Structural basis for DNA damage-dependent poly (ADP-ribosyl) ation by human PARP-1. Science, 2012, 336(6082): 728-732.
14.	de Murcia G, Huletsky A, Lamarre D, et al. Modulation of chromatin superstructure induced by poly (ADP-ribose) synthesis and degradation. J Biol Chem, 1986, 261(15): 7011-7017.
15.	Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature, 2001, 411(6835): 366-374.
16.	Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res, 2012, 72(21): 5588-5599.
17.	Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005, 434(7035): 917-921.
18.	Jasin M, Rothstein R. Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol, 2013, 5(11): a012740.
19.	Ashworth A, Lord CJ, Reis-Filho JS. Genetic interactions in cancer progression and treatment. Cell, 2011, 145(1): 30-38.
20.	赵伟, 殷雪, 朱小东, 等. 聚腺苷二磷酸核糖聚合酶-1抑制剂对乳腺癌易感基因突变乳腺癌细胞放射敏感性的影响及调控机制. 中华放射医学与防护杂志, 2016, 36(3): 168-172.
21.	蔡思源, 唐子执, 曾鸣, 等. DNA损伤应答靶向抑制剂对卵巢癌细胞的化疗增敏作用. 四川大学学报(医学版), 2016, 47(3): 316-320, 336.
22.	Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer, 2004, 4(10): 814-819.
23.	McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res, 2006, 66(16): 8109-8115.
24.	Daniel RA, Rozanska AL, Mulligan EA, et al. Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly (ADP-ribose) polymerase inhibitor AG-014699. Br J Cancer, 2010, 103(10): 1588-1596.
25.	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(4): 371-382.
26.	Turk AA, Wisinski KB. PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside. Cancer, 2018, 124(12): 2498-2506.
27.	No authors listed]. First PARP inhibitor Ok’d for breast cancer. Cancer Discov, 2018, 8(3): 256-257.
28.	Mateo J, Moreno V, Gupta A, et al. An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib. Target Oncol, 2016, 11(3): 401-415.
29.	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(9737): 235-244.
30.	Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med, 2017, 377(6): 523-533.
31.	杨君义. 治疗卵巢癌新药-多腺苷二磷酸核糖聚合酶抑制剂rucaparib. 中国新药与临床杂志, 2018, 37(2): 74-77.
32.	Drew Y, Ledermann J, Hall G, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly (ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer, 2016, 114(7): 723-730.
33.	Wilson RH, Evans TJ, Middleton MR, et al. A phase Ⅰ study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br J Cancer, 2017, 116(7): 884-892.
34.	Durmus S, Sparidans RW, van Esch A, et al. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699). Pharm Res, 2015, 32(1): 37-46.
35.	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(9): 882-892.
36.	Scott LJ. Niraparib: First global approval. Drugs, 2017, 77(9): 1029-1034.
37.	Konstantinopoulos PA, Sachdev JC, Schwartzberg L, et al. Dose-finding combination study of niraparib and pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC) (TOPACIO/Keynote-162). Ann Oncol, 2017, 28(5): 406.
38.	Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med, 2016, 375(1): 23-34.
39.	Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol, 2018, 19(4): 497-509.
40.	Litton J K, Scoggins M, Ramirez D L, et al. A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation. Ann Oncol, 2016, 27(suppl_60): vi43-vi67.
41.	Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med, 2018, 379(8): 753-763.
42.	Knezevic CE, Wright G, Rix LLR, et al. Proteome-wide profiling of clinical PARP inhibitors reveals compound-specific secondary targets. Cell Chem Biol, 2016, 23(12): 1490-1503.
43.	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(3): 244-250.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res, 2007, 13(15 Pt 1): 4429-4434.
3. Curigliano G, Goldhirsch A. The triple-negative subtype: new ideas for the poorest prognosis breast cancer. J Natl Cancer Inst Monogr, 2011, 2011(43): 108-110.
4. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med, 2010, 363(20): 1938-1948.
5. Bayraktar S, Gutierrez-Barrera AM, Liu D, et al. Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations. Breast Cancer Res Treat, 2011, 130(1): 145-153.
6. King MC, Marks JH, Mandell JB, et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 2003, 302(5645): 643-646.
7. Ashworth 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(22): 3785-3790.
8. 李文新. BRCA-1和PARP-1在三阴乳腺癌中表达及意义. 内蒙古医科大学学报, 2017, 39(6): 483-489.
9. Ohmoto A, Yachida S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther, 2017, 10: 5195-5208.
10. Rouleau M, Patel A, Hendzel MJ, et al. PARP inhibition: PARP1 and beyond. Nat Rev Cancer, 2010, 10(4): 293-301.
11. Ashworth A, Lord CJ. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors? Nat Rev Clin Oncol, 2018, 15(9): 564-576.
12. Nijman SM. Synthetic lethality: general principles, utility and detection using genetic screens in human cells. FEBS Lett, 2011, 585(1): 1-6.
13. Langelier MF, Planck JL, Roy S, et al. Structural basis for DNA damage-dependent poly (ADP-ribosyl) ation by human PARP-1. Science, 2012, 336(6082): 728-732.
14. de Murcia G, Huletsky A, Lamarre D, et al. Modulation of chromatin superstructure induced by poly (ADP-ribose) synthesis and degradation. J Biol Chem, 1986, 261(15): 7011-7017.
15. Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature, 2001, 411(6835): 366-374.
16. Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res, 2012, 72(21): 5588-5599.
17. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 2005, 434(7035): 917-921.
18. Jasin M, Rothstein R. Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol, 2013, 5(11): a012740.
19. Ashworth A, Lord CJ, Reis-Filho JS. Genetic interactions in cancer progression and treatment. Cell, 2011, 145(1): 30-38.
20. 赵伟, 殷雪, 朱小东, 等. 聚腺苷二磷酸核糖聚合酶-1抑制剂对乳腺癌易感基因突变乳腺癌细胞放射敏感性的影响及调控机制. 中华放射医学与防护杂志, 2016, 36(3): 168-172.
21. 蔡思源, 唐子执, 曾鸣, 等. DNA损伤应答靶向抑制剂对卵巢癌细胞的化疗增敏作用. 四川大学学报(医学版), 2016, 47(3): 316-320, 336.
22. Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer, 2004, 4(10): 814-819.
23. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res, 2006, 66(16): 8109-8115.
24. Daniel RA, Rozanska AL, Mulligan EA, et al. Central nervous system penetration and enhancement of temozolomide activity in childhood medulloblastoma models by poly (ADP-ribose) polymerase inhibitor AG-014699. Br J Cancer, 2010, 103(10): 1588-1596.
25. 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(4): 371-382.
26. Turk AA, Wisinski KB. PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside. Cancer, 2018, 124(12): 2498-2506.
27. No authors listed]. First PARP inhibitor Ok’d for breast cancer. Cancer Discov, 2018, 8(3): 256-257.
28. Mateo J, Moreno V, Gupta A, et al. An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib. Target Oncol, 2016, 11(3): 401-415.
29. 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(9737): 235-244.
30. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med, 2017, 377(6): 523-533.
31. 杨君义. 治疗卵巢癌新药-多腺苷二磷酸核糖聚合酶抑制剂rucaparib. 中国新药与临床杂志, 2018, 37(2): 74-77.
32. Drew Y, Ledermann J, Hall G, et al. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly (ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br J Cancer, 2016, 114(7): 723-730.
33. Wilson RH, Evans TJ, Middleton MR, et al. A phase Ⅰ study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours. Br J Cancer, 2017, 116(7): 884-892.
34. Durmus S, Sparidans RW, van Esch A, et al. Breast cancer resistance protein (BCRP/ABCG2) and P-glycoprotein (P-GP/ABCB1) restrict oral availability and brain accumulation of the PARP inhibitor rucaparib (AG-014699). Pharm Res, 2015, 32(1): 37-46.
35. 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(9): 882-892.
36. Scott LJ. Niraparib: First global approval. Drugs, 2017, 77(9): 1029-1034.
37. Konstantinopoulos PA, Sachdev JC, Schwartzberg L, et al. Dose-finding combination study of niraparib and pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC) (TOPACIO/Keynote-162). Ann Oncol, 2017, 28(5): 406.
38. Rugo HS, Olopade OI, DeMichele A, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med, 2016, 375(1): 23-34.
39. Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol, 2018, 19(4): 497-509.
40. Litton J K, Scoggins M, Ramirez D L, et al. A pilot study of neoadjuvant talazoparib for early-stage breast cancer patients with a BRCA mutation. Ann Oncol, 2016, 27(suppl_60): vi43-vi67.
41. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med, 2018, 379(8): 753-763.
42. Knezevic CE, Wright G, Rix LLR, et al. Proteome-wide profiling of clinical PARP inhibitors reveals compound-specific secondary targets. Cell Chem Biol, 2016, 23(12): 1490-1503.
43. 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(3): 244-250.

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Current researches on PARP inhibitors and its treatment of germline BRCA mutated breast cancer

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