Radiotherapy is widely used to treat many different types of cancer. While highly effective at killing cancer cells, radiotherapy can also damage surrounding healthy tissues, causing side effects that may persist long after treatment. These risks often limit the dose of radiotherapy that clinicians can safely deliver.
One approach to improving outcomes is to combine radiotherapy with drugs that selectively increase the sensitivity of tumour cells to radiation. Such radiosensitising treatments have the potential to improve tumour control without increasing damage to normal tissues.
The new study focuses on the potential of DNA polymerase theta (Polθ) in this setting. Polθ is an important enzyme involved in the repair of DNA double strand breaks (DSBs). Previous work from the Higgins lab demonstrated that inhibiting Polθ is a safe and effective approach for tumour selective radiosensitation in preclinical models. However, no clinically actionable biomarkers existed to identify patients most likely to benefit.
To understand how tumour cell heterogeneity influences this response, the team examined the effects of Polθ inhibition across a large panel of cancer cell lines. They demonstrated substantial radiosensitisation in 72% of cell lines tested, although the magnitude of the effect varied considerably, with some models showing minimal or no response.
The researchers therefore set out to identify the genetic factors that determine sensitivity to Polθ-mediated radiosensitisation. Using a CRISPR knockout screen targeting 2,776 genes involved in DNA damage responses, the team identified several genes which impacted sensitivity to radiotherapy, Polθ inhibition, and the combination of both treatments. Among the strongest findings was the identification of SHLD2 as a key suppressor of Polθ inhibitor-induced radiosensitisation.
To understand the clinical relevance of SHLD2, the team analysed patient tumour datasets and found that the gene is frequently lost in prostate cancer, with up to 10% of patient samples showing homozygous deletions.
Using SHLD2-deficient prostate cancer cell line, the team demonstrated that loss of SHLD2 increased sensitivity to radiotherapy alone, consistent with the gene's established role in DNA repair. Importantly, SHLD2 deficiency substantially enhanced the radiosensitising effects of Polθ inhibition. In SHLD2-deficient xenograft models, Polθ inhibition and radiotherapy significantly reduced tumour growth and prolonged survival, compared with radiotherapy alone. In contrast, relatively little additional benefit of Polθ inhibition was observed in SHLD2-proficient tumours.
"We believe that SHLD2 deficiency increases tumour dependence on Polθ-mediated repair following radiotherapy by limiting the ability of cells to cope with DNA damage through standard repair pathways" said Professor Geoff Higgins, Malcolm and Margaret Howat Professor of Clinical Oncology at the University of Oxford. "SHLD2 loss therefore represents a novel collateral vulnerability that could be exploited through combined treatment with Polθ inhibitors and radiotherapy."
© Gonzalo Rodriguez BerrigueteSHLD2 loss creates a therapeutically actionable dependence on Pol to repair DNA damage induced by radiation
The findings suggest that SHLD2 status could serve as a predictive biomarker to identify patients most likely to benefit from Polθ inhibitor-radiotherapy combinations. The study provides strong preclinical evidence supporting the clinical investigation of this combination strategy in patients with SHLD2-deficient cancers.
SHLD2 loss is a synthetic vulnerability to Polθ inhibition combined with radiotherapy was published in Science Advances on 12th June2026.