Study: Enzyme USP15 May Predict PARP Inhibitor Response in Breast, Pancreatic Cancers

The deubiquitylating enzyme USP15 may be a potential biomarker for therapeutic treatments using poly-(ADP-ribose) polymerase (PARP) inhibitors in cancers, according to a new study published in Nature Communications.

USP15 is a member of the largest subfamily of cysteine protease deubiquitinases (DUBs) that is aberrantly regulated or mutated in many cancers. DUBs play important roles in maintaining genome stability and human disease, according to the study. USP15, specifically, has been previously implicated in tumor growth factor-β and 1 morphogenetic protein response, antiviral immune response, T cell response, and neuroinflammation, according to the study. The Cancer Genome Atlas suggests that USP15 deletions occur in 16% of breast cancers and 5% of pancreatic cancers.

According to their findings, the researchers indicated that USP15 plays a crucial role in homologous recombination (HR), which is a major pathway to repair DNA damage and cancer cell response to PARP inhibitors. In the study, the authors found that USP15 targets BARD1, the major binding partner of the BRCA1 gene. The study also showed patients carried USP15 mutations that disrupted USP15-BARD1 interaction, with these cancer cells being more sensitive to PARP inhibitors, a new class of drugs.

PARP inhibitors have shown clinical efficacy as a treatment in the management of patients with BRCA mutations. Recent research has also suggested its efficacy in cancers without BRCA mutations, as well. However, biomarkers are needed to accurately identify tumors that are most likely to respond to this therapy.

“With this study, we validate the role of USP15 in maintaining genome stability and tumor suppression and inform novel treatments for breast cancer,” senior study author Huadong Pei, PhD, assistant professor of biochemistry and molecular medicine at the GW School of Medicine and Health Sciences, said in a press release about the study. “With consistent research and progress of current studies, we will gain a stronger understanding and a more comprehensive view of USP15 functions in cancer and their role in future treatment strategies.”

Expanding and identifying populations that carried USP15 mutations affecting its functions in HR may result in improving clinical outcomes, the researchers explained in the study.

In previous studies, USP15 has been reported to be deeply deleted in 26.7% of patients with pancreatic cancer. Additionally, a loss or significant decrease of USP15 expression was also seen in a high percentage of pancreatic cancer cell lines, which increases the cells’ sensitivity to PARP inhibitors. The researchers concluded that their findings may also implicate USP15 as a biomarker for PARP inhibitor treatment in pancreatic cancers.

Reference

Peng Y, Liao Q, Tan W, et al. The deubiquitylating enzyme USP16 regulates homologous recombination repair and cancer cell response to PARP inhibitors. Nature Communications. 2019. https://www.nature.com/articles/s41467-019-09232-8#Sec1.