The polymerase θ inhibitor novobiocin, which induces a synthetic lethality in cancer cells, has recently been approved for clinical evaluation as a possible treatment for BRCA1/2 mutant cancers. Researchers led by Ludwig Harvard’s Geoffrey Shapiro examined how the drug affects the tumor microenvironment in mouse models of BRCA1-deficient breast cancer and BRCA2-deficient pancreatic cancer. They reported in a March issue of Nature Communications that the drug causes chromosomal damage in cancer cells that results in the accumulation of micronuclei, which are free-floating bits of chromosomes. This activates the cGAS/STING pathway, an innate sensing system for cytoplasmic DNA that alerts the immune system to viral infection or DNA damage. cGAS/STING signaling led to the production of type 1 interferons, the activation of dendritic cells and an influx of killer T cells into the tumor microenvironment in mice. Novobiocin also boosted the expression of PD-L1 by cancer cells, an adaptive response to thwart T cell attack. The researchers showed that depleting killer T cells compromised the efficacy of novobiocin, while adding anti-PD1 immunotherapy enhanced anti-tumor effects in the mice. Geoff and his colleagues argue that their results provide a rationale for a clinical trial evaluating the combination of novobiocin and checkpoint blockade immunotherapy in patients with BRCA1/2 mutant cancers.
Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer
Nature Communications, 2023 March 13