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Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib
Anneleen Daemen1, Denise M Wolf, James E Korkola
1Laboratory Medicine, University of California San Francisco, 2340 Sutter Street Box 0808, San Francisco, CA 94115, USA. anneleen.daemen@gmail.com
Abstract:
Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in DNA repair. PARP inhibitors can act as chemosensitizers, or operate on the principle of synthetic lethality when used as single agent. Clinical trials have shown drugs in this class to be promising for BRCA mutation carriers. We postulated that inability to demonstrate response in non-BRCA carriers in which BRCA is inactivated by other mechanisms or with deficiency in homologous recombination for DNA repair is due to lack of molecular markers that define a responding subpopulation. We identified candidate markers for this purpose for olaparib (AstraZeneca) by measuring inhibitory effects of nine concentrations of olaparib in 22 breast cancer cell lines and identifying features in transcriptional and genome copy number profiles that were significantly correlated with response. We emphasized in this discovery process genes involved in DNA repair. We found that the cell lines that were sensitive to olaparib had a significant lower copy number of BRCA1 compared to the resistant cell lines (p value 0.012). In addition, we discovered seven genes from DNA repair pathways whose transcriptional levels were associated with response. These included five genes (BRCA1, MRE11A, NBS1, TDG, and XPA) whose transcript levels were associated with resistance and two genes (CHEK2 and MK2) whose transcript levels were associated with sensitivity. We developed an algorithm to predict response using the seven-gene transcription levels and applied it to 1,846 invasive breast cancer samples from 8 U133A/plus 2 (Affymetrix) data sets and found that 8-21 % of patients would be predicted to be responsive to olaparib. A similar response frequency was predicted in 536 samples analyzed on an Agilent platform. Importantly, tumors predicted to respond were enriched in basal subtype tumors. Our studies support clinical evaluation of the utility of our seven-gene signature as a predictor of response to olaparib.
Insights
Researchers identified a seven-gene signature to predict response to olaparib, a PARP inhibitor, in breast cancer. This signature could help identify patients likely to benefit from this DNA repair-targeted therapy.
Area of Science:
- Molecular biology
- Genomics
- Oncology
Background:
- Poly(ADP-ribose) polymerase (PARP) inhibitors show promise in BRCA-mutated cancers.
- Identifying responsive non-BRCA populations requires molecular markers for DNA repair deficiencies.
- Olaparib is a PARP inhibitor used in cancer therapy.
Purpose of the Study:
- To identify molecular markers predicting response to olaparib in breast cancer.
- To develop a predictive algorithm for olaparib response based on DNA repair gene profiles.
Main Methods:
- Assessed olaparib sensitivity across 22 breast cancer cell lines.
- Analyzed transcriptional and copy number profiles, focusing on DNA repair genes.
- Developed and validated a seven-gene signature algorithm using large patient datasets (Affymetrix and Agilent platforms).
Main Results:
- Lower BRCA1 copy number correlated with olaparib sensitivity.
- A seven-gene signature (including BRCA1, MRE11A, NBS1, TDG, XPA, CHEK2, MK2) was identified, with specific transcript levels associated with resistance or sensitivity.
- The algorithm predicted 8-21% of invasive breast cancer patients as responsive, with enrichment in basal subtype tumors.
Conclusions:
- A novel seven-gene signature can predict response to olaparib in breast cancer.
- This signature may identify patients with DNA repair deficiencies who could benefit from olaparib.
- Further clinical evaluation of this predictive signature is warranted.
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