Breast Cancer Research and Treatment

, Volume 147, Issue 1, pp 81–94

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

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

DOI: 10.1007/s10549-014-3085-5

Cite this article as:
Feng, F.Y., Speers, C., Liu, M. et al. Breast Cancer Res Treat (2014) 147: 81. doi:10.1007/s10549-014-3085-5

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.

Keywords

Breast cancer Radiation PARP1 inhibition DNA repair Biomarker 

Supplementary material

10549_2014_3085_MOESM1_ESM.pdf (2 mb)
Supplementary material 1 (PDF 1999 kb)

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Felix Y. Feng
    • 1
    • 2
    • 3
  • Corey Speers
    • 1
  • Meilan Liu
    • 1
  • William C. Jackson
    • 1
  • Dominic Moon
    • 1
  • Jacob Rinkinen
    • 1
  • Kari Wilder-Romans
    • 1
  • Reshma Jagsi
    • 1
    • 3
  • Lori J. Pierce
    • 1
    • 3
  1. 1.Department of Radiation OncologyUniversity of MichiganAnn ArborUSA
  2. 2.Michigan Center for Translational PathologyUniversity of MichiganAnn ArborUSA
  3. 3.Comprehensive Cancer CenterUniversity of MichiganAnn ArborUSA

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