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Shedding Light on Resistance to PARP Inhibitors in Patients With Breast Cancer

By: Cordi Craig
Posted: Monday, January 7, 2019

Patients with breast cancer who express specific BRCA1 mutations may not respond to PARP inhibitors, concluded a new study in Cell Reports. The results of a mouse model indicated that certain BRCA1-mutant alleles and their protein products affected the PARP inhibitor resistance route acquired by cancer cells.

“PARP inhibitor resistance is a challenge in treating cancers, and... a common mechanism of resistance may be more likely to arise in cancers with specific classes of BRCA1 mutations,” lead author Neil Johnson, PhD, of the Fox Chase Cancer Center, Philadelphia, stated in a recent institutional press release. “BRCA1-mutant cancers that are less receptive to this resistance mechanism could have prolonged therapeutic benefit from PARP inhibitor treatments.”

Using a mouse model and a panel of BRCA1-mutant cancer cell lines, the authors found that the 53BP1 gene knockout may aid in the embryonic viability of mice with BRCA1-mutant cell lines. This loss of 53BPI provides different levels of PARP inhibitor resistance. Additionally, the study shows that without hypomorphic BRCA1 proteins to retain an interaction with PALP2, there is inefficient RAD51 loading and suboptimal homologous recombination, causing PARP inhibitor sensitivity.

Future clinical studies are necessary to investigate potential relationships between BRCA1 mutations and particular PARP inhibitor resistance pathways, the authors concluded.

Disclosure: The study authors reported no conflicts of interest.



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