title: Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer.
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.
authors.affiliation: Department of Radiation Oncology, University of Michigan, 1500 East Medical Center Drive, UHB2C490-SPC5010, Ann Arbor, MI, 48109-5010, USA, ffeng@umich.edu.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.forename: Corey
authors.initials: C
authors.lastname: Speers
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.forename: William C
authors.initials: WC
authors.lastname: Jackson
authors.forename: Dominic
authors.initials: D
authors.lastname: Moon
authors.forename: Jacob
authors.initials: J
authors.lastname: Rinkinen
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.forename: Reshma
authors.initials: R
authors.lastname: Jagsi
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pierce
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; C521013:veliparib