Targeting Chemotherapy-Resistant Ovarian Cancer
Posted: Tuesday, February 19, 2019
According to a report published in the Journal of Cell Biology, TPX2 and Aurora A, a mitotic kinase complex, may bind to 53BP1, a chromatin-associated protein that regulates DNA damage response. The study authors suggest that this combination creates a mechanism that mimics the effects of BRCA proteins and may restore tumor susceptibility to chemotherapy drugs, providing a path toward improving the effectiveness of PARP inhibitors and preventing chemotherapy resistance in patients with ovarian cancer.
“Our work suggests the presence of a feedback mechanism by which 53BP1 is regulated by a novel binding partner and uncovers a unique role for 53BP1 in replication fork stability,” Nima Mosammaparast, MD, PhD, of Washington University, St. Louis, and colleagues concluded.
The protein complex appeared to play a role in repairing damaged DNA and replication fork stability by counteracting 53BP1 activity. Removing TPX2 and Aurora A compromised DNA end resection, BRCA1 and Rad51 recruitment, and homologous recombination. Furthermore, when exposed to replication stress, the loss of TPX2 and Aurora A caused the deprotection of stalled replication forks, which functioned in parallel to BRCA1. The simultaneous loss of 53BP1 restores the recruitment of BRCA and Rad51 and fork instability.
“There are inhibitors to Aurora A already in clinical trials for other types of cancer such as lymphoma and melanoma,” commented Dr. Mosammaparast in an institutional press release. “We could combine an Aurora inhibitor and a PARP inhibitor to more effectively target these cancers. I am working on getting funding to do such a study.”
Disclosure: The study authors reported no conflicts of interest.