POLQ Inhibitors May Treat PARP Inhibitor-Resistant BRCA-Mutated Cancers

A new class of targeted cancer drugs, DNA polymerase theta (POLQ) inhibitor, have the potential to treat patients whose tumors have BRCA mutations, according to a study published in Nature Communications. These drugs can kill cancer cells that are resistant to PARP inhibitors, an existing therapy for patients with BRCA mutations.

Prior to this research, it was known that genetically removing the POLQ protein killed cells with BRCA gene defects, but no drug had been identified that prevented POLQ from functioning. The current study identified prototype drugs that not only stop POLQ from working, but also kill BRCA-mutated cancer cells. Both BRCA genes and POLQ are involved in repairing DNA; cancer cells are capable of surviving without one, but if both are blocked or have their genes disabled, cancer cells are no longer capable of repairing their DNA and they die.

“Men and women with a change in 1 of their BRCA genes are at greater risk of being diagnosed with breast cancer, and around 5% of the 55,000 cases of breast cancer diagnosed in [the United Kingdom] each year are caused by an inherited altered gene, which includes BRCA1 and BRCA2 genes,” said Simon Vincent, PhD, in a press release. “It's therefore hugely exciting that POLQ inhibitors could provide a targeted treatment option for people whose cancer is caused by altered BRCA genes. As a targeted treatment, we hope that POLQ inhibitors could be a kinder alternative, with less [adverse] effects than current treatment options.”

The investigators found that POLQ inhibitors prevented BRCA-mutated cancer cells from repairing their DNA, but had no such effect on healthy cells, suggesting that these drugs could offer a treatment for cancer with relatively few adverse effects. Further, in laboratory tests combining POLQ inhibitors with PARP inhibitors, the researchers found that not only were PARP inhibitors effective at a lower dose, but POLQ inhibitors were also capable of shrinking BRCA-mutant cancers that had stopped responding to PARP inhibitors. This suggests POLQ inhibitors could act as an alternative treatment in situations where PARP inhibitors are no longer effective. According to investigators, using both drugs in combination could prevent the emergence of PARP inhibitor resistance altogether.

“Drug resistance is a major hurdle that we must tackle to stop women dying from breast cancer, so it is also exciting that POLQ inhibitors offer a hope of overcoming resistance in some cases,” Vincent said in the release. “We hope that future research will confirm that POLQ inhibitors can benefit people with breast cancer in these ways.”

REFERENCE

New drug class could treat range of cancers with faulty BRCA genes [news release]. EurekAlert; June 17, 2021. Accessed June 18, 2021. https://www.eurekalert.org/pub_releases/2021-06/iocr-ndc061621.php