Targeting Backup DNA Repair in Cancer

Without BRCA1 or BRCA2, cancer cells are vulnerable to DNA damage: Their ability to fix breaks in both DNA strands, via the error-free method of homologous recombination (HR), is considerably impaired. They depend instead on DNA repair regulated by PARP, a pathway scientists have long been trying to suppress: It was only recently, in December 2014, that the FDA approved the first PARP inhibitor, olaparib (Lynparza; AstraZeneca), for advanced BRCA-mutant ovarian cancer.

Two separate studies shed light on a key player in this backup repair strategy: DNA polymerase θ (Polθ, encoded by POLQ), which promotes alternative non–homologous end joining (alt-NHEJ), a repair process rife with errors. In one study, upregulation of Polθ was observed in HR-deficient ovarian cancer cell lines—when depleted of Polθ, these cells became hypersensitive to PARP inhibition and cytotoxic drugs. Embryos from crossbred HR-deficient and Polθ-deficient mice were not viable, while in human osteosarcoma cells, suppressing Polθ or PARP reduced the efficiency of alt-NHEJ, indicating that both are required for this form of DNA repair.

“Polθ is crucial for the survival of tumors where HR is impaired, and therefore an attractive therapeutic target,” says senior author Alan D'Andrea, MD, co-director of Dana-Farber Cancer Institute's Center for DNA Damage and Repair in Boston, MA.

In another study, inhibiting Polθ reduced dysfunctional chromosome fusions and translocations by keeping alt-NHEJ in check. However, when Polθ was suppressed in cells lacking BRCA1 and BRCA2, chromosomal aberrations increased significantly, compromising cell survival. So, despite being error-prone, alt-NHEJ mediated by Polθ can be considered “a salvage pathway that prevents genomic havoc in cells with compromised HR, by resolving unrepaired lesions,” says senior author Agnel Sfeir, PhD, an assistant professor at New York University's Skirball Institute of Biomolecular Medicine.

Both studies were also the first to show that Polθ's recruitment to DNA damage sites occurs through PARP, although the precise mechanism remains unknown.

One reason targeting Polθ holds promise, D'Andrea says, is that multiple routes of PARP-inhibitor resistance are already known, including cancer cells regaining functional HR as a result of secondary BRCA mutations or loss of the protein 53BP1. “Even if tumors evade PARP inhibitors, it's likely that some will still be sensitive to Polθ suppression,” he says.

“Importantly, while PARP is ubiquitous, Polθ is minimally expressed in normal cells,” Sfeir adds, “which means inhibiting Polθ should produce fewer side effects and be more tumor-specific.”

Besides providing a rationale for developing Polθ-targeted therapies, these studies indicate that more patients could potentially benefit from PARP inhibitors. “Germline mutations in BRCA1 or BRCA2 induce a profound HR defect, but drugs like olaparib may also be useful in treating tumors with more subtle HR deficiencies,” D'Andrea explains—for instance, from mutations in other genes along the BRCA pathway. “Perhaps Polθ is upregulated when any of these genes are disrupted and could predict PARP-inhibitor response,” he says.

D'Andrea plans to investigate this possibility; his team and Sfeir's also hope to uncover additional elements of PARP-regulated DNA repair, even as they continue probing Polθ's molecular dynamics.