Used to flying fast and loose with their DNA repair capabilities, drug-resistant breast cancer cells may soon get a rude awakening from a new class of drugs.
Scientists at Artios Pharma and the Institute of Cancer Research, London discovered a small molecule that binds to and inhibits the DNA repair polymerase Polθ, killing BRCA1 and BRCA2 mutant cancer cells. By targeting this class of proteins that have not been druggable before, Polθ inhibitors may be able to treat BRCA-mutant cancers that have developed resistance to the best available treatment: Poly (ADP-ribose) polymerase (PARP) inhibitors.
“Clearly, PARP inhibitors have been very successful, but all patients at some point will progress, sadly. So, understanding the resistance mechanisms becomes important so [that] we can consider other pathways to target,” said Graeme Smith, Chief Scientific Officer at Artios Pharma and one of the senior authors of the Nature Communications study describing the new class of drugs (1).
Cells tend to lose their DNA repair processes when they become cancerous. BRCA1 and BRCA2 help cells perform homologous recombination to repair a DNA break, but if they become mutated, other DNA repair proteins like PARP1, DNA ligase III, and Polθ can take over. This backup DNA repair mechanism called theta-mediated end-joining (TMEJ) is more error-prone than homologous recombination, but it gets the job done, which is enough for cancer cells.
PARP inhibitors work by impeding this backup DNA repair pathway, leading to cancer cell death. For BRCA-mutant cancers that have found a way to circumvent PARP inhibitors, clinicians need another treatment strategy. For that, they looked to Polθ.
“It's been in the literature as an interesting target for about 10 years,” Smith said. Prior research using CRISPR knockouts and RNAi gene silencing showed that loss of Polθ in BRCA1 or BRCA2 mutant cells killed the cancer cells, but scientists had not yet discovered any small molecules that could be used as drugs to inhibit Polθ.
“There's not really any precedent for targeting DNA repair polymerases such as Polθ. It’s not like a kinase,” Smith explained. “We’ve been drugging kinases for 30 years or so, so there's a great wealth of understanding on how to make a kinase inhibitor.”
By screening through approximately 650,000 compounds, Smith and his team discovered not one, but multiple Polθ inhibitors. The compound they describe in this study, ART558, inhibits Polθ by binding to its catalytic domain. ART558 does not inhibit any other human DNA polymerase, and it is a potent and selective Polθ inhibitor. When the scientists treated BRCA2 deficient cells with ART558 alone, more of the cancer cells died compared to cells in the control condition. Treating BRCA2 cells with ART558 in combination with a PARP inhibitor, Olaparib, resulted in even more cancer cell death. ART558 also killed BRCA1 deficient cells that had developed resistance to PARP.
When the team tested the metabolic stability of ART558 in rat microsomes in vitro, they found that the microsomes cleared the drug quickly, meaning that ART558 likely would not be effective in vivo. But another Polθ inhibitor, ART812, had better stability and exhibited less clearance than ART558 in vitro. ART812 also significantly inhibited PARP-resistant BRCA1 mutant tumor growth in rats.
Smith and his colleagues have not stopped at ART812. “We've done further optimization work, and we have another compound, which we'll be moving towards the clinic in the latter part of this year,” Smith said.
Thomas Helleday, a cancer researcher at the Karolinska Institute who was not involved in the study, but who wrote a commentary on the paper (2), thought that the work was rock solid. “The results are really in line with what has been proposed using genetics earlier,” he said.
Smith is excited to get the team’s leading Polθ inhibitor into clinical trials, and he hopes that it will help treat multiple types of BRCA-mutant cancers including breast, ovarian, prostate, and pancreatic cancers. Smith also hopes to test the Polθ inhibitors in combination with DNA damaging agents.
“I think there's still a lot to be explored and uncovered,” he said. “There's quite a lot of options and opportunities for Polθ inhibitors.”
1. Zatreanu, D. et al. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nat Commun 12, 3636 (2021).
2. Helleday, T. Polθ inhibitors unchained. Nat Cancer 2, 581-583 (2021).