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HomeHealth ConditionsCancerCan we target BRCA1-defecient ovarian cancer?

Can we target BRCA1-defecient ovarian cancer?

A recent study in Journal of Cell Biology revealed a new molecular node that could be pharmacologically targeted to treat BRCA-1 deficient ovarian cancers.

Environmental stresses can introduce breaks within our genomic DNA. Such errors are highly deleterious to the cells. Therefore our cells deploy multiple genome repair mechanisms in order to avoid the occurrence of genome damage.

BRCA-1 and 53BP1 are two key repair proteins that are made specifically to repair DNA double strands breaks. These proteins are primarily responsible for repairing DNA damage through two biological pathways. The activation of these proteins upon DNA damage and can either give the cells enough time to repair the damage or kill the damaged cells before they transform into cancer.

Cells that carry mutations that compromise the function of BRCA-1 lack the ability to repair genome damage. This, over time, can transform into cancer. In fact, individuals with mutated BRCA-1 have dramatically increased susceptibility to develop breast and ovarian cancer.

While cells with defective BRCA-1 or those that lack BRCA-1 are highly sensitive to a class of drugs called PARP inhibitors, many cancers can develop resistance to these inhibitors. This is potentially due to the development of alternative pathways that allow cancer cells to persist despite the pharmacological blockade of BRCA-1-defective and BRCA-1 deficient cancer cells.

Scientists from Washington University School of Medicine in St. Louis, United States have identified a compensatory mechanism that could play a part in fueling chemo-resistance in BRCA-1 deficient cancers. They published their results in the Journal of Cell Biology.

The scientists stumbled on this discovery while studying the cellular function of a different protein called 53BP1. They found that two proteins called TPX2 and Aurora A form a complex which then inhibits the activity of 53BP1. The activation of 53BP1 is thought to be an alternative DNA damage repair mechanism that kicks in once BRCA-1 function has been compromised.

The authors suggested that TPX2 and Aurora A could provide a new set of targets to kill BRCA-1 deficient cancer cells. Given that inhibitors for Aurora A are already FDA-approved, the study is generating lot of attention in terms due to discovery of a molecular node that could be targeted in BRCA-1 deficient cancers.

Written by Vinayak Khattar, Ph.D., M.B.A

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

Vinayak Khattar PhD MBA
Vinayak Khattar PhD MBA
Vinayak Khattar completed his Master of Biotechnology at D.Y. Patil University in India. He received his Ph.D. in Cancer Biology at the University of Alabama at Birmingham (UAB) and then completed his M.B.A from the UAB Collat School of Business. His research interests lie in identifying mechanisms that dictate protein stability in cancer cells, immuno-oncology, and bone biology. He has seven peer-reviewed publications, over 40 citations, and three awards. He likes to watch Netflix documentaries with his family during his free time.
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