Cancer biomarker for efficacy of PARP inhibitor discovered

Since tumors often exhibit unique defects in the pathway of DNA damage response (DDR), the identification of the molecular mechanisms that underlie the way cells repair various lesions of the body. DNA is essential for selecting the appropriate clinical treatments. Inhibitors of poly- (ADP-ribose) polymerase (PARP) are examples of drugs that are successfully exploiting the DDR pathway and have become an effective anti-cancer treatment for people with BRCA mutations. Yet, in recent years, more and more evidence suggests that PARP inhibitors may be very effective for ovarian tumors lacking BRCA mutations, however, the mechanism of this phenomenon does not occur. been clearly defined. Researchers at the George Washington University Cancer Center (GW) have identified a potential genomic signature that may increase the benefits of PARP inhibitors.

"Inhibitors of poly- (ADP-ribose) polymerase (PARPi) selectively kill bad and ovarian cancers with homologous recombination (HR) defects caused by mutations in BRCA1 / 2", said authors. "There is also clinical evidence for the utility of PARPi in bad and ovarian cancers without BRCA mutation, but the underlying mechanism is not clear."

The results of the new study published today in Nature Communications through an article titled "The USP15 deubiquitylation enzyme regulates repair by homologous recombination and the response of cancer cells to PARP inhibitors" – revealed that the enzyme USP15 could potentially lead to new treatments for bad and pancreatic cancers.

"With this study, we validate the role of USP15 in maintaining genome stability and tumor suppression and inform new bad cancer treatments," said lead researcher Huadong Pei, PhD, Assistant Professor of Biochemistry and Molecular Medicine at the GW School of Medicine Health Sciences. "Through consistent research and the progress of ongoing studies, we will be able to better understand and understand the USP15 functions in cancer and their role in future treatment strategies."

The atlas of the cancer genome indicates that deletions of the USP15 enzyme occur in 16% of bad cancers and in 5% of pancreatic cancers. Studies have shown that USP15 mutations badociated with cancer increase the sensitivity of PARP inhibitors in cancer cells. The GW team discovered that the USP15 regulates homologous recombination, one of the main repair pathways for DNA damage affecting broth strands of the double helix, and the response of cancer cells to PARP inhibitors.

"Mechanically, USP15 is recruited by MDC1 for double-stranded DNA breaks (ADS), which requires the FHA domain of MDC1 and the phosphorylated Ser678 of USP15," the authors write. "Subsequently, USP15 deubiquitin the BARD1 BRCT domain and promotes BARD1-HP1γ interaction, which results in the retention of BRCA1 / BARD1 at the level of DSBs. USP15 knockout mice exhibit genomic instability in vivo. In addition, USP15 mutations badociated with cancer, badociated with a decrease in USP15-BARD1 interaction, increase the sensitivity of PARP inhibitors in cancer cells. "

USP15 is part of a group of ubiquitinating enzymes, responsible for suppressing ubiquitin chains of proteins and other molecules, which play an important role in maintaining genome stability . Based on their research, Pei and his team believe that the USP15 could work in the same way as the USP4 enzyme, which plays a role in DNA repair by Pei's group Four years ago.

"USP15 is a potential biomarker for pancreatic cancer treatments, as well as bad and ovarian cancer," said lead researcher Yihan Peng, a PhD student at Pei's lab.

Subsequently, the research team will use patient-derived tissue transplant models to examine the impact of the USP15 enzyme on the response of radiochemotherapy. In addition, they will perform high throughput screening for USP15 inhibitors.

"Our results identify a new regulator of homologous recombination, which is a potential biomarker for therapeutic treatment using PARP inhibitors in cancers," the authors concluded.