PARP

Overview

Members of the poly (ADP-ribose) polymerase (PARP) family of proteins are involved in a number of cellular processes such as DNA repair, genomic stability, cell cycle progression, and apoptosis.1,2

  • A primary role of PARP1 is to detect single-strand DNA breaks and promote one of the mechanisms for DNA repair, Base Excision Repair (BER).3
  • PARP also plays a role in modulating the repair of double strand breaks.4
  • PARP activity has also been implicated in regulating gene expression through effects on chromatin architecture, transcriptional activator and coactivator functions, and maintaining DNA methylation patterns.2,5,6

Implications in cancer

PARP inhibitors are thought to exert their antitumor activity by7:

  • Inhibiting the catalytic activity of PARP1 and PARP2
  • Trapping PARP1 and PARP2 on damaged DNA and preventing DNA repair, replication, and transcription, leading to replication fork collapse

Inhibition of PARP 1 and 2 may lead to accumulation of single- and double-strand DNA breaks and apoptosis in:

  • Tumor cells that are exposed to DNA-damaging agents.8
  • Tumor cells that are deficient in one or more of the DNA repair mechanisms such as homologous recombination.1

Oncogenic Expression

Lung Cancer

Platinum-based combinations form the cornerstone of chemotherapy for non-small cell lung cancer (NSCLC), as initial therapy and as second-line after targeted therapies have failed.9

  • Few patients (~30%) respond to chemotherapy.8,10
  • Elevated DNA repair capacity is associated with drug resistance in NSCLC.11
  • PARP inhibitors may sensitize tumor cells to the effects of DNA-damaging chemotherapy.12

Although small-cell lung cancer (SCLC) may be more responsive to initial chemotherapy and radiation, patients quickly relapse with treatment-resistant disease.13

  • Activation of DNA repair pathways in response to these treatment modalities contributes to resistance.14
  • PARP1 is highly overexpressed in SCLC.13

Breast Cancer

HR-DSR is dependent on functional BRCA 1 and 2 pathways. PARP inhibition leads to replication fork collapse at sites of single-strand breaks, resulting in double-strand breaks. In BRCA-deficient breast cancer, the normal HR-DSR pathway is disrupted, leading to accumulation of unrepaired double-strand breaks and cell death.1,4

  • Dependence on PARP-mediated repair may contribute to resistance to DNA-damaging chemotherapeutic agents in BRCA-deficient breast cancer.1

Triple negative breast cancer (TNBC) shares many clinical and pathological similarities with BRCA-deficient breast cancer, including dysfunctional DNA repair mechanisms.1

  • There is a high frequency of PARP1 overexpression in TNBC, suggesting that PARP1 may play a role in promoting disease progression.15-17

Overexpression and upregulation of PARP1 in breast cancers is associated with a worse prognosis.16


Ovarian Cancer

Approximately 50% of high-grade serous ovarian cancers exhibit defects in HR and DNA repair pathways.18,19 Defects have also been detected in nonserous histologies, including clear-cell, endometrioid, and carcinosarcomas.19

  • PARP expression has been detected in up to 60% of epithelial ovarian tumor specimens.20
  • Patients with concomitantly high levels of PARP, FANCD2 and P53 protein expression have been shown to be at increased risk of early ovarian cancer recurrence and platinum resistance.20
  1. Anders CK, Winer EP, Ford JM, et al. Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. Clin Cancer Res. 2010;16:4702-4710.
  2. Caiafa P, Guastafierro T, Zampieri M. Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. FASEB J. 2009;23(3):672-678.
  3. Dantzer F, de La Rubia G, Menissier-De Murcia J, et al. Base excision repair is impaired in mammalian cells lacking poly(ADP-ribose) polymerase-1. Biochemistry. 2000;39:7559-7569.
  4. Audebert M, Salles B, Calsou P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem. 2004;279(53):55117-55126.
  5. Lodhi N, Kossenkov AV, Tulin AV. Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark. Nucleic Acids Res. 2014;42(11):7028-7038.
  6. Ali SO, Khan FA, Galindo-Campos MA, Yélamos J. Understanding specific functions of PARP-2: new lessons for cancer therapy. Am J Cancer Res. 2016;6(9):1842-1863.
  7. Shen Y, Aoyagi-Scharber M, Wang B. Trapping poly(ADP-ribose) polymerase. J Pharmacol Exp Ther. 2015;353(3):446-457.
  8. Plummer ER, Calvert H. Targeting poly(ADP-ribose) polymerase: a two-armed strategy for cancer therapy. Clin Cancer Res. 2007;13:6252-6256.
  9. Lwin Z, Weirss JR, Gandara D. The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era. J Thorac Dis. 2013;5(S5):S556-S564.
  10. Bosken CH, Wei Q, Amos CI, Spitz MR. An analysis of DNA repair as a determinant of survival in patients with non-small-cell lung cancer. J Natl Cancer Inst. 2002;94(14):1091-1099.
  11. Zeng-Rong N, Paterson J, Alpert L, et al. Elevated DNA repair capacity is associated with intrinsic resistance of lung cancer to chemotherapy. Cancer Res. 1995;55:4760-4764.
  12. Spigel DR. PARP inhibitors in lung cancer. J Thorac Oncol. 2012;7(12):S392-S393.
  13. Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012;2:798-811.
  14. O'Grady S, Finn SP, Cuffe S, et al. The role of DNA repair pathways in cisplatin resistant lung cancer. Cancer Treat Rev. 2014;40(10):1161-1170.
  15. Goncalves A, Finetti P, Sabatier R, et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Res Treat. 2011;127:273-281.
  16. Rojo F, Garcia-Parra J, Zazo S, et al. Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol. 2012;23:1156-1164.
  17. Ossovskaya V, Koo IC, Kaldjian EP, Alvares C, Sherman BM. Upregulation of poly (ADP-Ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer. 2010;1:812-821.
  18. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609-615.
  19. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5(11):1137-1154.
  20. Wysham WZ, Mhawech-Fauceglia P, Li H, et al. BRCAness profile of sporadic ovarian cancer predicts disease recurrence. PLoS One. 2012;7(1):e30042.

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