Skip to main content

Advertisement

SpringerLink
Log in

Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Sustained locoregional control of breast cancer is a significant issue for certain patients. Inhibition of PARP1 is a promising strategy for radiosensitization (RS). We sought to optimize therapy with PARP1 inhibition and radiation (RT) by establishing the most effective treatment schedule, degree of PARP1-mediated RS, and identify early biomarkers predictive of efficacy in breast cancer models. Using clonogenic survival assays, we assessed intrinsic radiosensitivity and RS induced by PARP1 inhibition in breast cancer cell lines. Potential biomarkers of response were evaluated using western blotting, flow cytometry, and immunofluorescence with validation in vivo using tumor xenograft experiments. Across a panel of BC and normal breast epithelial cell lines, the PARP1 inhibitor ABT-888 preferentially radiosensitizes breast cancer (vs. normal) cells with enhancement ratios (EnhR) up to 2.3 independent of intrinsic BC subtype or BRCA mutational status. Concurrent and adjuvant therapy resulted in the highest EnhR of all schedules tested. The degree of RS did not correlate with pretreatment markers of PARP1 activity, DNA damage/repair, or cell cycle distribution. Increases in PARP1 activity 24 h after RT were associated with sensitivity after combination treatment. Findings were confirmed in breast cancer xenograft models. Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT independent of BC subtype or BRCA1 mutational status and that PARP1 activity may serve as a clinically relevant biomarker of response. These studies have led to a clinical trial (TBCRC024) incorporating intratreatment biomarker analyses of PARP1 inhibitors and RT in breast cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Farmer H et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921

    Article  CAS  PubMed  Google Scholar 

  2. Ashworth A (2008) 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 26(22):3785–3790

    Article  CAS  PubMed  Google Scholar 

  3. Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819

    Article  CAS  PubMed  Google Scholar 

  4. Dantzer F et al (2000) Base excision repair is impaired in mammalian cells lacking poly(ADP-ribose) polymerase-1. Biochemistry 39(25):7559–7569

    Article  CAS  PubMed  Google Scholar 

  5. Mitchell J, Smith GC, Curtin NJ (2009) Poly(ADP-ribose) polymerase-1 and DNA-dependent protein kinase have equivalent roles in double strand break repair following ionizing radiation. Int J Radiat Oncol Biol Phys 75(5):1520–1527

    Article  CAS  PubMed  Google Scholar 

  6. Schiewer MJ et al (2012) Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov 2(12):1134–1149

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Weaver AN, Yang ES (2013) Beyond DNA repair: additional functions of PARP-1 in cancer. Front Oncol 3:290

    Article  PubMed Central  PubMed  Google Scholar 

  8. Haber JE (1999) DNA recombination: the replication connection. Trends Biochem Sci 24(7):271–275

    Article  CAS  PubMed  Google Scholar 

  9. Albert JM et al (2007) Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res 13(10):3033–3042

    Article  CAS  PubMed  Google Scholar 

  10. Chalmers A et al (2004) PARP-1, PARP-2, and the cellular response to low doses of ionizing radiation. Int J Radiat Oncol Biol Phys 58(2):410–419

    Article  CAS  PubMed  Google Scholar 

  11. Powell C et al (2010) Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. Cancer Treat Rev 36(7):566–575

    Article  CAS  PubMed  Google Scholar 

  12. Donawho CK et al (2007) ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res 13(9):2728–2737

    Article  CAS  PubMed  Google Scholar 

  13. Rehman S, Reddy CA, Tendulkar RD (2012) Modern outcomes of inflammatory breast cancer. Int J Radiat Oncol Biol Phys 84(3):619–624

    Article  PubMed  Google Scholar 

  14. Buchholz TA et al (2002) Predictors of local-regional recurrence after neoadjuvant chemotherapy and mastectomy without radiation. J Clin Oncol 20(1):17–23

    Article  CAS  PubMed  Google Scholar 

  15. Mamounas EP et al (2012) Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27. J Clin Oncol 30(32):3960–3966

    Article  PubMed Central  PubMed  Google Scholar 

  16. Foundation for the National Institutes of Health (2009) I-SPY 2 TRIAL: neoadjuvant and personalized adaptive novel agents to treat breast cancer. ClinicalTrials.gov Identifier: NCT01042379. http://www.clinicaltrials.gov. Accessed 13 Oct 2013

  17. Cancer Research UK (2013) Rucaparib(CO-338;Formally Called AG-014699 or PF-0136738) in treating patients with locally advanced or metastatic breast cancer or advanced ovarian cancer. ClinicalTrials.gov identifier: NCT00664781. http://www.clinicaltrials.gov. Accessed 13 Oct 2013

  18. Gelmon KA et al (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12(9):852–861

    Article  CAS  PubMed  Google Scholar 

  19. Lee J, Annunziata AC, Minasian LM, Zujewski J, Prindiville SA, Kotz HL, Squires J, Houston ND, Ji JJ, Yu M, Doroshow JH, Kohn EC (2011) Phase I study of the PARP inhibitor olaparib (O) in combination with carboplatin (C) in BRCA1/2 mutation carriers with breast (Br) or ovarian (Ov) cancer (Ca) [abstract]. J Clin Oncol 29(Suppl 15):2520

    Google Scholar 

  20. Viswanathan S, Wesolowski W, Layman RM, Alejandra G, Miller B, Chalmers JJ, Bejastani S, Zhao W, Pierluigu G, Cotrill J, Phelps MA, Schaaf LJ, Geyer SM, Hall N, Knopp MV, Shapiro CL, Villalona-Calero MA, Chen A, Grever, Ramaswamy B (2011) A phase I dose-escalation study of ABT-888 (veliparib) in combination with carboplatin in HER2-negative metastatic breast cancer (MBC). J Clin Oncol 29(15):TPS106

    Google Scholar 

  21. Yap TA, Omlin A, de Bono JS (2013) Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol 31(12):1592–1605

    Article  CAS  PubMed  Google Scholar 

  22. de Bono JS, Ashworth A (2010) Translating cancer research into targeted therapeutics. Nature 467(7315):543–549

    Article  PubMed  Google Scholar 

  23. Horstmann E et al (2005) Risks and benefits of phase 1 oncology trials, 1991 through 2002. N Engl J Med 352(9):895–904

    Article  CAS  PubMed  Google Scholar 

  24. Tsimberidou AM et al (2012) Personalized medicine in a phase I clinical trials program: the MD Anderson cancer center initiative. Clin Cancer Res 18(22):6373–6383

    Article  CAS  PubMed  Google Scholar 

  25. Baselga J et al (1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14(3):737–744

    CAS  PubMed  Google Scholar 

  26. O’Brien SG et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348(11):994–1004

    Article  PubMed  Google Scholar 

  27. Flaherty KT et al (2010) Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 363(9):809–819

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Ji J, Lee MP, Kadota M, Zhang Y, Parchment RE, Tomaszewski JE, Doroshow JH (2011) Pharmacodynamic and pathway analysis of three presumed inhibitors of poly (ADP-ribose) polymerase: ABT-888, AZD2281, and BSI201 [abstract]. In: Proceedings of the AACR 102nd annual meeting, vol 52, 2011

  30. Han S et al (2013) Targeted radiosensitization of ETS fusion-positive prostate cancer through PARP1 inhibition. Neoplasia 15(10):1207–1217

    Article  PubMed Central  PubMed  Google Scholar 

  31. Fertil B et al (1984) Mean inactivation dose: a useful concept for intercomparison of human cell survival curves. Radiat Res 99(1):73–84

    Article  CAS  PubMed  Google Scholar 

  32. Brenner JC et al (2011) Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 19(5):664–678

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Wei D et al (2013) Inhibition of protein phosphatase 2A radiosensitizes pancreatic cancers by modulating CDC25C/CDK1 and homologous recombination repair. Clin Cancer Res 19(16):4422–4432

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Neve RM et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10(6):515–527

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Hollestelle A et al (2010) Distinct gene mutation profiles among luminal-type and basal-type breast cancer cell lines. Breast Cancer Res Treat 121(1):53–64

    Article  PubMed  Google Scholar 

  36. Elstrodt F et al (2006) BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res 66(1):41–45

    Article  CAS  PubMed  Google Scholar 

  37. Willers H et al (2009) Utility of DNA repair protein foci for the detection of putative BRCA1 pathway defects in breast cancer biopsies. Mol Cancer Res 7(8):1304–1309

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Oplustilova L et al (2012) Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment. Cell Cycle 11(20):3837–3850

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Barker CA, Powell SN (2010) Enhancing radiotherapy through a greater understanding of homologous recombination. Semin Radiat Oncol 20(4):267–273 e3

    Article  PubMed  Google Scholar 

  40. Pawlik TM, Keyomarsi K (2004) Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 59(4):928–942

    Article  PubMed  Google Scholar 

  41. McCabe N et al (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66(16):8109–8115

    Article  CAS  PubMed  Google Scholar 

  42. Veuger SJ et al (2003) Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res 63(18):6008–6015

    CAS  PubMed  Google Scholar 

  43. Hegan DC, Glazer PM (2011) Mechanism of radiosensitization by inhibitors of poly(ADP-ribose) polymerase (PARP) [abstract]. In: Proceedings of the 102nd annual meeting of the american association for cancer research, vol 71, suppl 8, 2011

  44. Ju BG et al (2006) A topoisomerase IIbeta-mediated dsDNA break required for regulated transcription. Science 312(5781):1798–1802

    Article  CAS  PubMed  Google Scholar 

  45. Zhang F et al (2013) Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor alpha-dependent gene transcription. J Biol Chem 288(16):11348–11357

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Riaz M et al (2009) Low-risk susceptibility alleles in 40 human breast cancer cell lines. BMC Cancer 9:236

    Article  PubMed Central  PubMed  Google Scholar 

  47. Hall RE et al (1994) MDA-MB-453, an androgen-responsive human breast carcinoma cell line with high level androgen receptor expression. Eur J Cancer 30A(4):484–490

    Article  CAS  PubMed  Google Scholar 

  48. Poulin R et al (1989) Down-regulation of estrogen receptors by androgens in the ZR-75-1 human breast cancer cell line. Endocrinology 125(1):392–399

    Article  CAS  PubMed  Google Scholar 

  49. Hickey TE et al (2012) Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol 26(8):1252–1267

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Saberi A et al (2007) RAD18 and poly(ADP-ribose) polymerase independently suppress the access of nonhomologous end joining to double-strand breaks and facilitate homologous recombination-mediated repair. Mol Cell Biol 27(7):2562–2571

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Breast Cancer Research Foundation and Komen for the Cure for funding of these studies. We would also like to thank Steven Kronenberg for his excellent assistance in preparing the figures for publication.

Conflict of interest

The authors declare no conflict of interest in this publication.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, UHB2C490-SPC5010, Ann Arbor, MI, 48109-5010, USA

    Felix Y. Feng, Corey Speers, Meilan Liu, William C. Jackson, Dominic Moon, Jacob Rinkinen, Kari Wilder-Romans, Reshma Jagsi & Lori J. Pierce

  2. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA

    Felix Y. Feng

  3. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    Felix Y. Feng, Reshma Jagsi & Lori J. Pierce

Authors
  1. Felix Y. Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corey Speers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meilan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William C. Jackson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dominic Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jacob Rinkinen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kari Wilder-Romans
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Reshma Jagsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lori J. Pierce
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lori J. Pierce.

Additional information

Felix Y. Feng and Corey Speers contributed equally.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1999 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, F.Y., Speers, C., Liu, M. et al. Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer. Breast Cancer Res Treat 147, 81–94 (2014). https://doi.org/10.1007/s10549-014-3085-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-014-3085-5

Keywords

Search

Navigation