OLAPARIB MAY BE USEFUL IN HIGH POLQ CANCERS

Last December, the U.S. Food and Drug Administration (FDA) approved olaparib (Lynparza) in the treatment of advanced ovarian cancer in women with BRCA1 or BRCA2 gene mutations. Now, a laboratory study by Ceccaldi et al has found that the drug may also be effective in breast and ovarian tumors that express abnormally high levels of the polymerase q (POLQ) enzyme. The results suggest that POLQ may be a potential target for novel therapies. The study is published in Nature.

Study Methodology

To examine changes in polymerase activity between tumors and normal tissues, the researchers screened polymerase gene expression profiles in a large numbers of cancers. Gene set enrichment analysis revealed specific and recurrent POLQ in epithelial ovarian cancers. POLQ was upregulated in a grade-dependent manner and its expression positively correlated with numerous mediators of homologous recombination. Because POLQ has been suggested to play a role in DNA repair, the researchers investigated a potential role for POLQ in homologous recombination repair.

Study Findings

The researchers found an inverse correlation between homologous recombination activity and POLQ expression in epithelial ovarian cancers. Knockdown of POLQ in homologous recombination-proficient cells upregulates homologous recombination activity and RAD51 nucleofilament assembly, while knockdown of POLQ in homologous recombination-deficient epithelial ovarian cancers enhances cell death, according to the study abstract.

“Consistent with these results, genetic inactivation of [a homologous recombination] gene (Fancd2) and POLQ in mice results in embryonic lethality. Moreover, POLQ contains RAD51 binding motifs and it blocks RAD51-mediated recombination,” wrote the study authors. “Our results reveal a synthetic lethal relationship between the [homologous recombination] pathway and [POLQ]-mediated repair in [epithelial ovarian cancers], and identify POLQ as a novel druggable target for cancer therapy.”

“About 10% to 15% of ovarian cancers arise in women who have inherited mutations in BRCA1 or BRCA2,” said Alan D’Andrea, MD, Co-Director of the Gene Therapy Center at Dana-Farber Cancer Institute and senior author of the study, in a statement. “Although olaparib is often effective in this group of patients, we haven’t known precisely how it works. By uncovering part of the biological machinery that olaparib operates on, we now have a rational for making it and similar drugs available to a broader population of patients.” In addition, said Dr. D’Andrea, “The discovery that cancer cells with BRCA mutations are utterly dependent on POLQ for their continued survival—and that normal cells are not—suggests that POLQ could be an ideal target for novel therapies. We’re working on developing such therapies now.”

Dr. D’Andrea is the corresponding author for the Nature article.

Funding for this study was provided by grants from the National Institutes of Health, the Ovarian Cancer Research Fellowship, and the Breast Cancer Research Foundation.

The study authors declared no conflicts of interest.