Pathway-enriched gene signature associated with 53BP1 response to PARP inhibition in triple-negative breast cancer

Saima Hassan, Amanda Esch, Tiera Liby, Joe Gray, Laura Heiser

Research output: Contribution to journalArticle

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Abstract

Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose–response measures of cell viability, an EC50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC50 values for both 53BP1 metrics strongly correlated with IC50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle–associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition.

Original languageEnglish (US)
Pages (from-to)2892-2901
Number of pages10
JournalMolecular Cancer Therapeutics
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

Triple Negative Breast Neoplasms
Genes
DNA Damage
Biomarkers
Breast Neoplasms
Phenotype
Therapeutics
Heterografts
DNA Repair
Inhibitory Concentration 50
Fluorescent Antibody Technique
Cell Survival
Clinical Trials
Apoptosis
Cell Line
Poly(ADP-ribose) Polymerase Inhibitors
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pathway-enriched gene signature associated with 53BP1 response to PARP inhibition in triple-negative breast cancer. / Hassan, Saima; Esch, Amanda; Liby, Tiera; Gray, Joe; Heiser, Laura.

In: Molecular Cancer Therapeutics, Vol. 16, No. 12, 01.12.2017, p. 2892-2901.

Research output: Contribution to journalArticle

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