New Insights into BRCA-1 Deficient Ovarian Cancers

Study Overview

A recent publication in the *Journal of Cell Biology* has unveiled a potential molecular target for treating BRCA-1 deficient ovarian cancers. This discovery may lead to new pharmacological strategies aimed at combating this type of cancer.

The Role of Genome Repair Mechanisms

Cells encounter environmental stresses that can cause breaks in genomic DNA, which can severely affect cellular function. To protect against these detrimental errors, cells activate multiple genome repair mechanisms to prevent genomic damage. Among these, BRCA-1 and 53BP1 are crucial proteins responsible for repairing DNA double-strand breaks through two primary biological pathways. Upon DNA damage, these proteins can either provide the necessary time for cells to repair or induce cell death to prevent potential cancer transformation.

Impact of BRCA-1 Mutations

Cells with mutations that impair BRCA-1 functionality lose the capacity to effectively repair genomic damage, increasing the risk of cancer development over time. Individuals with BRCA-1 mutations face a significantly higher likelihood of developing breast and ovarian cancers.

Resistance to PARP Inhibitors

While BRCA-1 deficient cells are particularly vulnerable to a class of drugs known as PARP inhibitors, many cancers can acquire resistance to these treatments. This resistance may arise from the activation of alternative pathways that enable cancer cells to survive despite the pharmacological inhibition targeting BRCA-1.

Discovery of a Compensatory Mechanism

Researchers at Washington University School of Medicine in St. Louis have identified a compensatory mechanism that may contribute to chemotherapy resistance in BRCA-1 deficient cancers. Their findings, published in the *Journal of Cell Biology*, emerged during investigations into the cellular function of the protein 53BP1.

The Role of TPX2 and Aurora A

The study revealed that two proteins, TPX2 and Aurora A, form a complex that inhibits the activity of 53BP1. The activation of 53BP1 is believed to serve as an alternative DNA damage repair mechanism that becomes active when BRCA-1 function is compromised.

Potential for New Therapeutic Targets

The authors of the study propose that TPX2 and Aurora A may represent a new set of targets for eliminating BRCA-1 deficient cancer cells. Notably, existing FDA-approved inhibitors for Aurora A could facilitate the development of targeted therapies for these cancers, making this discovery particularly significant.

Reference

Byrum, A. K., Carvajal-Maldonado, D., Mudge, M. C., Valle-Garcia, D., Majid, M. C., Patel, R., . . . Mosammaparast, N. (2019). Mitotic regulators TPX2 and Aurora A protect DNA forks during replication stress by counteracting 53BP1 function. *J Cell Biol*, 218(2), 422-432. doi:10.1083/jcb.201803003