Targeting treatment-resistant BRCA-mutated tumors via the newly discovered POLQ pathway


PARP inhibitors like AstraZeneca’s Lynparza have been game-changing for some patients whose tumors have mutations in the BRCA gene, but those cancers invariably become resistant to the drugs. Now two separate groups of scientists are announcing the discovery of a new drug target that could be exploited to treat patients with drug-resistant, BRCA-mutated cancers.

Both teams are targeting an enzyme called POLQ, which tumors with mutations in BRCA1 and BRCA2 need to grow and survive. BRCA mutations have been linked to several cancers, including breast, ovarian and prostate cancer.

For one study, published in Nature Communications, scientists at the Institute of Cancer Research worked with Artios Pharma to study the effects of POLQ inhibitors on BRCA-mutated tumors. They developed small-molecule drugs to inhibit the enzyme and tested them in cancer cells, they reported in the journal Nature Communications.

The researchers found that POLQ inhibitors blocked the ability of BRCA-mutated cancer cells to repair their DNA, killing them. The drugs left normal cells unharmed. The POLQ inhibitors also worked in combination with PARP inhibitors, they reported.

They went on to test the POLQ inhibitors in rat models. The drugs shrank BRCA-mutated tumors that had stopped responding to PARP inhibitors, they said.

Artios is on track to launch clinical trials of a POLQ inhibitor by the end of this year, said study co-leader Graeme Smith, Ph.D., the company’s chief scientific officer, in a statement. “Our planned POLQ inhibitor clinical studies will leverage these results, exploring combination treatment with PARP inhibitors and different types of DNA damaging agents," he said in a statement.

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Meanwhile, researchers at Dana-Farber Cancer Institute said they may have found a way to target POLQ with an existing drug—one that first hit the market over a half-century ago.

The Dana-Farber team tested the antibiotic novobiocin in BRCA1- and BRCA2-mutated tumor cells and animal models. They found that the drug killed the tumor cells, including those that had grown resistant to PARP inhibitors. They published their results in the journal Nature Cancer.

Alan D'Andrea, M.D., co-senior author of the study, had published research in 2015 showing that BRCA-mutated tumors rely on POLQ. D’Andrea and his colleagues were surprised to uncover studies from the 1990s in which novobiocin was tested in cancer patients. A small subset of those patients saw their disease recede.

“At the time, no one knew what the drug's target was,” D'Andrea said in a statement. “Now we do, and, as a result, we have an indication of which patients are likely to be helped by it.”

Dana-Farber is now planning a clinical trial of novobiocin in patients with BRCA-mutated cancers who have become resistant to PARP inhibitors.