New resistance mechanism to PARP inhibitors revealed

The reasons why tumors with BRCA1 and BRCA2 mutations stop responding to PARP inhibitor drugs have been described by a new study.

Between 5% and 10% of breast and ovarian cancers can be attributed to inherited mutations in genes such as BRCA1 or BRCA2. For patients with these mutations, results have been encouraging with personalized therapy with PARP inhibitors, which are currently in clinical trials. Nevertheless, recent studies indicate that a fraction of these patients generate resistance to the drug, which leads them to stop responding to the treatment.

According to the researchers, the problem arises when the tumors, in addition to their mutations in BRCA1 and BRCA2, also contain secondary mutations in other proteins such as 53BP1 or PTIP. These proteins restrain DNA repair. In cases with these secondary mutations, the mutations compensate for each other. Then, the tumor cells recover the ability to repair their DNA and the drug stops working.

“This is one of the first studies to demonstrate that secondary mutations can make tumors resistant when faced with specific treatments like, in this case, PARP inhibitors,” said lead researcher Óscar Fernández-Capetillo, PhD, of the Spanish National Cancer Research Center in Madrid, Spain. The study was published in Cell (2013; doi:10.1016/j.cell.2013.05.023).

When the researchers compared different treatments, they observed that standard treatment with cisplatin was more efficient than personalized therapy for those tumors that have both BRCA1/2 mutations and also 53BP1 or PTIP mutations.

"These data indicate that only patients containing mutations in BRCA1 and/or BRCA2, but not in the secondary genes we have described, would be candidates for an effective personalized therapy with PARP inhibitors", explained Fernández-Capetillo. He concluded, "Our results suggest that 53BP1 and PTIP genes would need to be evaluated in patients with familial breast and ovarian cancer when deficiencies in the BRCA genes were present before deciding on their treatment".

In this context, researchers intend to warn health care providers in personalized medicine that the challenge, in addition to the search for markers of drug sensitivity for new pharmacologic compounds, also encompasses the search for secondary resistance markers. The aim would be to bring about significant improvements in treatment outcomes.
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