The Therapeutic Potential of PARP Inhibitors in Pancreatic Cancer

Öz

Pancreatic cancer is characterized by high mortality due to its aggressive nature, late diagnosis, and resistance to treatment. In recent years, targeting DNA repair mechanisms in cancer therapy—particularly through the use of PARP inhibitors—has shown promising potential. PARP enzymes play a critical role in the repair of DNA damage, and their inhibition can exert a strong tumour-suppressive effect, especially in the presence of BRCA mutations. This review discusses the mechanism of action, clinical application, and therapeutic effects of PARP inhibitors in pancreatic cancer. Additionally, it evaluates recent findings and research outcomes that may shed light on the future of targeted therapies.

Anahtar Kelimeler

• Pancreatic cancer
• PARP inhibitors
• targeted therapy
• molecular therapies
• anticancer drugs
• DNA repair
• genetic mutations
• and cancer therapy.

Pankreas Kanserinde PARP İnhibitör Tedavisinin Potansiyeli

Öz

Pankreas kanseri agresif seyri, geç teşhisi ve tedaviye dirençli yapısıyla kanser türleri arasında büyük bir morfoliteye sahiptir. Son yıllarda kanser teadvilerinde DNA onarım mekanizmalarının hedeflenmesi, özellikle PARP inhibitörleri ile geliştirilen tedaviler oldukça umut verici olmuştur. PARP enzimleri DNA hasarının onarılmasında önemli rol oynamaktadır. Bu enzimlerin baskılanması özellikle BRCA mutasyonlarının varlığında oldukça etkili bir tümör baskılayıcı etki yaratmaktadır. Bu derlemede pankreas kanserinde PARP inhibitörlerinin mekanizması, klinik kullanımı ve etki mekanizmaları ele alınmıştır. Ayrıca hedefe yönelik tedavilerin geleceğe ışık tutabilecek güncel bulgular ve araştırma sonuçları değerlendirilmiştir.

Anahtar Kelimeler

• Pankreas kanseri
• PARP inhibitörleri
• hedefli tedavi
• moleküler terapiler
• kanser ilaçları
• DNA tamiri
• genetik mutasyonlar ve kanser terapisi

Kaynakça

1. Akce, M., Zaidi, M. Y., Waller, E. K., El-Rayes, B. F., & Lesinski, G. B. (2018). The potential of CAR T cell therapy in pancreatic cancer. Frontiers in Immunology, 9, 2166.
2. Ashour, M. E., & Mosammaparast, N. (2021). Mechanisms of damage tolerance and repair during DNA replication. Nucleic Acids Research, 49(6), 3033–3047.
3. Barber, L. J., Sandhu, S., Chen, L., Campbell, J., Kozarewa, I., Fenwick, K., Assiotis, I., Rodrigues, D. N., Reis-Filho, J. S., & Moreno, V. (2013). Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. The Journal of Pathology, 229(3), 422–429.
4. Bell, S. P., & Dutta, A. (2002). DNA replication in eukaryotic cells. Annual Review of Biochemistry, 71(1), 333–374.
5. Bester, A. C., Roniger, M., Oren, Y. S., Im, M. M., Sarni, D., Chaoat, M., Bensimon, A., Zamir, G., Shewach, D. S., & Kerem, B. (2011). Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell, 145(3), 435–446.
6. Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., Vitale, L., Pelleri, M. C., Tassani, S., & Piva, F. (2013). An estimation of the number of cells in the human body. Annals of Human Biology, 40(6), 463–471.
7. Biankin, A. V, Waddell, N., Kassahn, K. S., Gingras, M.-C., Muthuswamy, L. B., Johns, A. L., Miller, D. K., Wilson, P. J., Patch, A.-M., & Wu, J. (2012). Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 491(7424), 399–405.
8. Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), 229–263.

9. Bryant, H. E., & Helleday, T. (2006). Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair. Nucleic Acids Research, 34(6), 1685–1691.
10. Bunting, S. F., Callén, E., Wong, N., Chen, H.-T., Polato, F., Gunn, A., Bothmer, A., Feldhahn, N., Fernandez-Capetillo, O., & Cao, L. (2010). 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell, 141(2), 243–254.
11. Buwenge, M., Macchia, G., Arcelli, A., Frakulli, R., Fuccio, L., Guerri, S., Grassi, E., Cammelli, S., Cellini, F., & Morganti, A. G. (2018). Stereotactic radiotherapy of pancreatic cancer: a systematic review on pain relief. Journal of Pain Research, 2169–2178.
12. Cao, L., Xu, X., Bunting, S. F., Liu, J., Wang, R.-H., Cao, L. L., Wu, J. J., Peng, T.-N., Chen, J., & Nussenzweig, A. (2009). A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Molecular Cell, 35(4), 534–541.
13. Choi, Y. E., Meghani, K., Brault, M.-E., Leclerc, L., He, Y. J., Day, T. A., Elias, K. M., Drapkin, R., Weinstock, D. M., & Dao, F. (2016). Platinum and PARP inhibitor resistance due to overexpression of microRNA-622 in BRCA1-mutant ovarian cancer. Cell Reports, 14(3), 429–439.
14. Curtin, N. J., & Szabo, C. (2020). Poly (ADP-ribose) polymerase inhibition: past, present and future. Nature Reviews Drug Discovery, 19(10), 711–736.
15. de Bono, J., Ramanathan, R. K., Mina, L., Chugh, R., Glaspy, J., Rafii, S., Kaye, S., Sachdev, J., Heymach, J., & Smith, D. C. (2017). Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discovery, 7(6), 620–629.
16. Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., & Ashworth, A. (2008). Resistance to therapy caused by intragenic deletion in BRCA2. Nature, 451(7182), 1111–1115. https://doi.org/10.1038/nature06548
17. Farmer, H., McCabe, H., Lord, C. J., Tutt, A. H. J., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M. B., Jackson, S. P., Smith, G. C. M., & Ashworth, A. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434(7035), 917–921. https://doi.org/10.1038/nature03445
18. Fong, P. C., Boss, D. S., Yap, T. A., Tutt, A., Wu, P., Mergui-Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., & O’Connor, M. J. (2009). Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. New England Journal of Medicine, 361(2), 123–134.
19. Genois, M.-M., Gagné, J.-P., Yasuhara, T., Jackson, J., Saxena, S., Langelier, M.-F., Ahel, I., Bedford, M. T., Pascal, J. M., & Vindigni, A. (2021). CARM1 regulates replication fork speed and stress response by stimulating PARP1. Molecular Cell, 81(4), 784–800.
20. Ghiorzo, P. (2014). Genetic predisposition to pancreatic cancer. World Journal of Gastroenterology: WJG, 20(31), 10778.
21. Gillen, S., Schuster, T., Meyer zum Büschenfelde, C., Friess, H., & Kleeff, J. (2010). Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Medicine, 7(4), e1000267.
22. Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J.-O., Hochhauser, D., Arnold, D., & Oh, D.-Y. (2019). Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. New England Journal of Medicine, 381(4), 317–327.
23. Goral, V. (2015). Pancreatic cancer: pathogenesis and diagnosis. Asian Pacific Journal of Cancer Prevention, 16(14), 5619–5624.
24. Görgülü, Ş. (2019). N-(4-asetilfenil)-2-(ariltiyo)asetamid ve N’-(3-hidroksi-4-metoksibenziliden)-2-(4-tosilpiperazin-1-il) asetohidrazit türevlerinin pankreas kanserinde antikanser etkilerinin PARP inhibitörleri ile karşılaştırılması. Anadolu Üniversitesi, Eskişehir.
25. Gunderson, C. C., & Moore, K. N. (2015). BRACAnalysis CDx as a companion diagnostic tool for Lynparza. Expert Review of Molecular Diagnostics, 15(9), 1111–1116.
26. Hahn, S. A., Greenhalf, B., Ellis, I., Sina-Frey, M., Rieder, H., Korte, B., Gerdes, B., Kress, R., Ziegler, A., & Raeburn, J. A. (2003). BRCA2 germline mutations in familial pancreatic carcinoma. Journal of the National Cancer Institute, 95(3), 214–221.
27. Hanahan, D. (2022). Hallmarks of Cancer: New Dimensions. Cancer Discovery, 12(1), 31–46. https://doi.org/10.1158/2159-8290.CD-21-1059
28. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70. https://doi.org/10.1016/S0092-8674(00)81683-9
29. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646–674. https://doi.org/10.1016/j.cell.2011.02.013
30. Hanzlikova, H., Kalasova, I., Demin, A. A., Pennicott, L. E., Cihlarova, Z., & Caldecott, K. W. (2018). The importance of poly (ADP-ribose) polymerase as a sensor of unligated Okazaki fragments during DNA replication. Molecular Cell, 71(2), 319–331.
31. Hashimoto, Y., Ray Chaudhuri, A., Lopes, M., & Costanzo, V. (2010). Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis. Nature Structural & Molecular Biology, 17(11), 1305–1311.
32. Huang, D., & Kraus, W. L. (2022). The expanding universe of PARP1-mediated molecular and therapeutic mechanisms. Molecular Cell, 82(12), 2315–2334.
33. Huang, R.-X., & Zhou, P.-K. (2020). DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduction and Targeted Therapy, 5(1), 60.
34. Ibrahim, Y. H., García-García, C., Serra, V., He, L., Torres-Lockhart, K., Prat, A., Anton, P., Cozar, P., Guzmán, M., & Grueso, J. (2012). PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discovery, 2(11), 1036–1047.
35. Ide, H., Shoulkamy, M. I., Nakano, T., Miyamoto-Matsubara, M., & Salem, A. M. H. (2011). Repair and biochemical effects of DNA–protein crosslinks. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 711(1–2), 113–122.
36. Jones, S., Hruban, R. H., Kamiyama, M., Borges, M., Zhang, X., Parsons, D. W., Lin, J. C.-H., Palmisano, E., Brune, K., & Jaffee, E. M. (2009). Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science, 324(5924), 217.
37. Jones, S., Zhang, X., Parsons, D. W., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., & Jimeno, A. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321(5897), 1801–1806.
38. Kaufman, B., Shapira-Frommer, R., Schmutzler, R. K., Audeh, M. W., Friedlander, M., Balmaña, J., Mitchell, G., Fried, G., Stemmer, S. M., & Hubert, A. (2015). Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of Clinical Oncology, 33(3), 244–250.
39. Kim, M. P., & Gallick, G. E. (2008). Gemcitabine resistance in pancreatic cancer: picking the key players. In Clinical Cancer Research (Vol. 14, Issue 5, pp. 1284–1285). American Association for Cancer Research.
40. Kindler, H. L., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., Park, J. O., Hochhauser, D., Arnold, D., & Oh, D.-Y. (2022). Overall survival results from the POLO trial: a phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer. Journal of Clinical Oncology, 40(34), 3929–3939.
41. Kleeff, J., Reiser, C., Hinz, U., Bachmann, J., Debus, J., Jaeger, D., Friess, H., & Büchler, M. W. (2007). Surgery for recurrent pancreatic ductal adenocarcinoma. Annals of Surgery, 245(4), 566–572.
42. Klein, A. P. (2021). Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nature Reviews Gastroenterology & Hepatology, 18(7), 493–502.
43. Krastev, D. B., Wicks, A. J., & Lord, C. J. (2021). PARP inhibitors–trapped in a toxic love affair. Cancer Research, 81(22), 5605–5607.
44. Kristeleit, R., Shapiro, G. I., Burris, H. A., Oza, A. M., LoRusso, P., Patel, M. R., Domchek, S. M., Balmaña, J., Drew, Y., & Chen, L. (2017). A phase I–II study of the oral PARP inhibitor rucaparib in patients with germline BRCA1/2-mutated ovarian carcinoma or other solid tumors. Clinical Cancer Research, 23(15), 4095–4106.
45. Langelier, M.-F., & Pascal, J. M. (2013). PARP-1 mechanism for coupling DNA damage detection to poly (ADP-ribose) synthesis. Current Opinion in Structural Biology, 23(1), 134–143.
46. Lord, C. J., & Ashworth, A. (2017). PARP inhibitors: Synthetic lethality in the clinic. Science, 355(6330), 1152–1158.
47. Lüscher, B., Ahel, I., Altmeyer, M., Ashworth, A., Bai, P., Chang, P., Cohen, M., Corda, D., Dantzer, F., Daugherty, M. D., Dawson, T. M., Dawson, V. L., Deindl, S., Fehr, A. R., Feijs, K. L. H., Filippov, D. V, Gagné, J.-P., Grimaldi, G., Guettler, S., … Ziegler, M. (2022). ADP-ribosyltransferases, an update on function and nomenclature. The FEBS Journal, 289(23), 7399–7410. https://doi.org/10.1111/febs.16142
48. Mackay, J. (2006). The cancer atlas. American Cancer Society.
49. Magdalou, I., Lopez, B. S., Pasero, P., & Lambert, S. A. E. (2014). The causes of replication stress and their consequences on genome stability and cell fate. Seminars in Cell & Developmental Biology, 30, 154–164.
50. Mirza, M. R., Pignata, S., & Ledermann, J. A. (2018). Latest clinical evidence and further development of PARP inhibitors in ovarian cancer. Annals of Oncology, 29(6), 1366–1376.
51. Murai, J., Huang, S.-Y. N., Renaud, A., Zhang, Y., Ji, J., Takeda, S., Morris, J., Teicher, B., Doroshow, J. H., & Pommier, Y. (2014). Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Molecular Cancer Therapeutics, 13(2), 433–443.
52. O’Sullivan, J., Tedim Ferreira, M., Gagné, J.-P., Sharma, A. K., Hendzel, M. J., Masson, J.-Y., & Poirier, G. G. (2019). Emerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation. Nature Communications, 10(1), 1182.
53. Ohmoto, A., & Yachida, S. (2017). Current status of poly (ADP-ribose) polymerase inhibitors and future directions. OncoTargets and Therapy, 5195–5208.
54. Pascal, J. M., & Ellenberger, T. (2015). The rise and fall of poly (ADP-ribose): an enzymatic perspective. DNA Repair, 32, 10–16.
55. Plummer, R. (2011). Poly (ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer? Breast Cancer Research, 13, 1–6.
56. Roberts, N. J., Jiao, Y., Yu, J., Kopelovich, L., Petersen, G. M., Bondy, M. L., Gallinger, S., Schwartz, A. G., Syngal, S., & Cote, M. L. (2012). ATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery, 2(1), 41–46.
57. Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004). Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual Review of Biochemistry, 73(1), 39–85.
58. Shen, Y., Aoyagi-Scharber, M., & Wang, B. (2015). Trapping poly (ADP-ribose) polymerase. The Journal of Pharmacology and Experimental Therapeutics, 353(3), 446–457.
59. Sheng, S., Margarida Bernardo, M., Dzinic, S. H., Chen, K., Heath, E. I., & Sakr, W. A. (2018). Tackling tumor heterogeneity and phenotypic plasticity in cancer precision medicine: our experience and a literature review. Cancer and Metastasis Reviews, 37(4), 655–663.
60. Shroff, R. T., Hendifar, A., McWilliams, R. R., Geva, R., Epelbaum, R., Rolfe, L., Goble, S., Lin, K. K., Biankin, A. V, & Giordano, H. (2018). Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation. JCO Precision Oncology, 2, 1–15.
61. Singhi, A. D., George, B., Greenbowe, J. R., Chung, J., Suh, J., Maitra, A., Klempner, S. J., Hendifar, A., Milind, J. M., & Golan, T. (2019). Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. Gastroenterology, 156(8), 2242–2253.
62. Somyajit, K., Spies, J., Coscia, F., Kirik, U., Rask, M.-B., Lee, J.-H., Neelsen, K. J., Mund, A., Jensen, L. J., & Paull, T. T. (2021). Homology-directed repair protects the replicating genome from metabolic assaults. Developmental Cell, 56(4), 461–477.
63. Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249.
64. Teloni, F., & Altmeyer, M. (2015). Readers of poly (ADP-ribose): designed to be fit for purpose. Nucleic Acids Research, 44(3), 993–1006.
65. Tubbs, A., & Nussenzweig, A. (2017). Endogenous DNA damage as a source of genomic instability in cancer. Cell, 168(4), 644–656.
66. Tuli, R., Shiao, S. L., Nissen, N, Tighiouart, M., Kim, S., Osipov, A., Bryant, M., Ristow, L., Placencio-Hickok, V., & Hoffman, D. (2019). A phase 1 study of veliparib, a PARP-1/2 inhibitor, with gemcitabine and radiotherapy in locally advanced pancreatic cancer. EBioMedicine, 40, 375–381.
67. Virág, L., Robaszkiewicz, A., Rodriguez-Vargas, J. M., & Oliver, F. J. (2013). Poly (ADP-ribose) signaling in cell death. Molecular Aspects of Medicine, 34(6), 1153–1167.
68. Yazinski, S. A., Comaills, V., Buisson, R., Genois, M.-M., Nguyen, H. D., Ho, C. K., Kwan, T. T., Morris, R., Lauffer, S., & Nussenzweig, A. (2017). ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes & Development, 31(3), 318–332.
69. Zeman, M. K., & Cimprich, K. A. (2014). Causes and consequences of replication stress. Nature Cell Biology, 16(1), 2–9.
70. Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A., & De Lange, T. (2013). 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science, 339(6120), 700–704.