91 Quick summary: Researchers have identified that the enzyme RNase H2 enables aggressive triple negative breast cancer cells to survive high levels of DNA replication stress and resist conventional therapies. Inhibiting this enzyme creates a dual therapeutic effect by directly damaging cancer cell DNA and activating the innate immune system to recruit T cells for a targeted attack on the tumour. These findings offer a significant breakthrough for healthcare practice by providing a foundation for new combination treatments that could substantially improve clinical outcomes and long term well being for patients facing this difficult to treat malignancy. Researchers at the University of Texas MD Anderson Cancer Center have identified a key enzyme, RNase H2, that helps triple-negative breast cancer (TNBC) cells survive high levels of DNA replication stress. Because many breast cancer therapies work by causing replication stress, these results suggest RNase H2 is a promising treatment target. The study, published in Cell Reports Medicine, was led by Shiaw-Yih Lin, Professor of Systems Biology. The findings reveal that RNase H2 directly damages cancer cell DNA while also activating the innate immune system to produce signals that attract T cells to attack the tumour. “Adding RNase H2 inhibition is a one-two punch that overcomes the adaptive mechanism that triple-negative breast cancer tumours leverage to survive replication stress and continue progressing,” Lin said. “Our findings show that this is a promising therapeutic strategy that lays the groundwork to meaningfully improve patient outcomes for this aggressive and difficult-to-treat subtype of breast cancer.” Replication stress is the slowing or stalling of DNA replication when cells copy their DNA. This causes structural DNA damage, such as single-strand DNA accumulation and the embedding of RNA pieces into DNA, leading to cell death. Many breast cancer therapies work by causing DNA replication stress, but TNBC cells somehow survive this stress and genomic instability, even at high levels. It has long been unclear how they adapt to this.. Since one of the major sources of replication stress is the accumulation of embedded RNA, the researchers focused on the RNase H2 enzyme, which normally removes stray RNA pieces that get mistakenly built into DNA to prevent DNA damage. The researchers found that RNase H2 is highly overexpressed in TNBC tumours and correlates with poor survival, suggesting it may contribute to the adaptive mechanism that enables cells to handle DNA replication stress. Either genetically silencing RNase H2 or blocking it with drugs increased the amount of DNA replication stress, leading to a strong antitumour response and suppression of TNBC tumour growth in vivo. Moreover, this had an immune-boosting effect, with DNA damage activating the innate immune system to send out signals that recruit T cells to attack the cancer. While these findings are preclinical, the use of RNase H2 inhibitors – some of which are currently in development – could one day become a strategy to improve outcomes for patients with this difficult-to-treat cancer. The study also showed that blocking RNase H2 boosts the effects of two existing classes of cancer drugs – ATR and PARP inhibitors – pointing to combination strategies that could be tested in future clinical trials.