Researchers Discover Mechanism for PARP Inhibitor Resistance

According to a recent study published online in Nature, researchers have identified molecular means by which some cancers caused by errors in the gene BRCA1 evade treatment by PARP inhibitors.

It is estimated that roughly 288,000 new cases of breast and ovarian cancer will be diagnosed in this year. Oftentimes, patients diagnosed with these types of cancer are treated with PARP inhibitors, which are designed to exploit the defects that make tumors with certain mutations especially deadly. However, this targeted approach sometimes fails to achieve a response among certain patients. To better understand this drug class, the research team, led by Titia de Lang, PhD, Leon Hess Professor at The Rockefeller University and colleagues, challenged previous assumptions about the mechanics by which PARP inhibitors succeed or fail to help patients.

Although a substantial number of ovarian and breast cancers are caused by harmful errors in the two most common human genomes, BRAC1 and BRAC2, this study specifically observed BRCA1. It is estimated that mutations in BRAC1 give women a roughly 72% chance of developing breast cancer and a 44% chance of developing ovarian cancer by age 80.

Researchers believe that a failed treatment response is due to a number of reasons, but Dr de Lang and colleagues linked the loss of the protein 53BP1 to possible resistance in BRAC1 cancer in particular.

“This is a complete shift in our understanding of the mechanism that underlies this form of treatment for BRCA1 cancers,” Dr de Lang explains in a press release.

The loss of the protein 53BP1 can make it possible for BRCA1-deficient cells to overcome their inherent defect. Although it isn’t clear why, this type of resistance can potentially emerge during or after PARP inhibitor treatment when some tumor cells thrive after mutating to lose 53BP1.

“In the big picture, this new insight into 53BP1's function and its role in drug resistance provides a foundation for advancements in PARP inhibitor therapy,” Mr Mirman explained in a statement.

According to the researcher team, the findings of this study may assist in the development of screening tests to see which tumors would best respond to PARP inhibitors or to determine which other drugs should or should not be given along with them—increasing the utility of PARP inhibitors.

—Julie Gould

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