Cross-platform pathway-based analysis identifies markers of response to the PARP inhibitor olaparib

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-012-2188-0) contains supplementary material, which is available to authorized users.

Comparative antiproliferative effects of iniparib and olaparib on a panel of triple-negative and non-triple-negative breast cancer cell lines

“…25 This panel included five genes, i.e., BRCA1, XPA, TDG, NBS1 and MRE11A, whose mRNAs were associated with resistance and two genes, i.e., MK2 and CHEK2, whose mRNAs correlated with sensitivity. However, as mentioned above, levels of BRCA1 mRNA, when treated as a single variable, did not show a statistically significant relation (i.e, at the 0.05 level) with sensitivity to olaparib.…”

Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer

“…Short tandem repeat (STR) DNA profiling (Genetica DNA Laboratories, Burlington, NC) performed in October 2014 prior to conduction of chemosensitivity experiments, confirmed cell line authenticity, and PCR analysis verified the absence of Mycoplasma. Molecular features of the cell lines, including gene cluster information (15,16), breast cancer subtype (15,17), mutational status for BRCA1/2, ATM, ATR (18,19), and PTEN deficiency status (20), are summarized in Supplementary Table S1.…”

Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

“…Larsen and colleagues analyzed 55 familial BRCA1/2 mutant and 128 sporadic breast tumors to derive a transcriptional signature that was able to predict BRCA mutant cancers in an independent data set (Larsen et al 2013). Other investigators have also used transcriptional profiles derived from cell lines with either known HR gene defects (Daemen et al 2012, Peng et al 2014 or PARPi sensitivity to generate BRCAness signatures.…”