Researchers Discover Mutations Behind Resistance to PARP Inhibitors Like Lynparza

Researchers Discover Mutations Behind Resistance to PARP Inhibitors Like Lynparza

Scientists have found mutations in the poly ADP-ribose polymerase (PARP) gene that cause resistance to PARP inhibitor therapies — such as Lynparza (olaparib) — in a mouse model and in one patient with ovarian cancer, according to a recent study.

Detection of these mutations could help physicians to predict which cancer patients are likely to develop a resistance to PARP inhibitors and to decide the best possible treatment.

The study, “Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance,” was published in the journal Nature Communications.

PARP enzymes act as DNA damage sensors, binding to the sites of DNA damage and leading to its repair. Cancer cells that have defects in other DNA repair mechanisms — such as those with mutated BRCA tumor suppressor genes, which cause 5.8% to 24.8% of all ovarian cancer cases — rely on PARP to survive and proliferate.

It is believed that PARP activity suppression leads to the accumulation of DNA damage and ultimately to the death of these cancer cells, making PARP inhibitors especially effective in patients with BRCA mutations.

Most clinical PARP inhibitors were shown to cause cell death not only through blocking PARP activity, but also by trapping PARP at the sites of DNA damage, to which the enzyme binds.

Lynparza, an oral inhibitor of PARP, was initially approved in 2014 as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer and BRCA mutations, but recent data supporting its effectiveness in women without BRCA mutations led to its approval, regardless of BRCA status.

To further investigate the mechanisms of PARP inhibitors, a team of researchers at The Institute of Cancer Research in London used the recent “CRIPSR-Cas9” gene editing technology — a defense mechanism found in bacteria that allows researchers to edit specific parts of the DNA — to generate and identify specific mutations that cause resistance to PARP inhibitors.

The approach involved generating mutations in specific sections of the PARP1 gene and tagging the resulting mutated proteins with a fluorescent protein so their responses to PARP inhibitors could be tracked.

Researchers identified specific PARP1 mutations that caused resistance to PARP inhibitors both in cultured cells and in tumor-bearing mouse models.

While talazoparib — a PARP inhibitor being developed for the treatment of breast cancer — delayed breast cancer growth and increased survival of mice with nonmutated breast cancer, it did not have any detectable effect in mice with PARP1-mutant breast tumors.

The newly discovered mutations were found to disrupt the ability of the PARP1 enzyme to bind to DNA, preventing PARP inhibitors from trapping PARP1 at the site of DNA damage.

To the researchers’ surprise, PARP1 mutations also caused resistance to PARP inhibitors in cancer cells with certain mutations in the BRCA1 gene. Additional analysis suggested that some residual BRCA1 function is retained in these cells, which seems to be enough to support some DNA repair and cell survival, despite the loss of PARP1 activity.

At the same time, the team identified a specific PARP1 mutation in an ovarian cancer patient who had developed a resistance to Lynparza. This mutation prevented the trapping mechanism of PARP inhibitors, “suggesting that such mutations can arise in patients and could potentially contribute to resistance,” they wrote.

“Testing for the mutations we have identified could offer even more personalised treatment for women with breast and ovarian cancer, by allowing doctors to judge whether and for how long olaparib [Lynparza] should be used,” Stephen Pettitt, MD, the study’s first author and a staff scientist in cancer genomics at The Institute of Cancer Research, said in a press release.

Scientists noted that further research is required to identify and examine more PARP1 mutations in patients, and that their gene-editing approach in this study could be used in the analysis of treatment-resistant mutations for other therapies and diseases.