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Adv."],"published-print":{"date-parts":[[2026,6,12]]},"abstract":"<jats:p>\n                    Inhibition of DNA polymerase theta (Pol\u03b8), an essential enzyme for repairing DNA double-strand breaks (DSBs) via microhomology-mediated end joining (MMEJ), has proven to be an exquisitely effective monotherapy in HR-deficient tumor models. In addition, Pol\u03b8 inhibition (Pol\u03b8i) can induce tumor-selective radiosensitization, but unlike its monotherapy use, no clinically actionable biomarkers have yet been identified to predict this effect. Here, we profiled 54 cancer cell lines and found that Pol\u03b8i induces substantial radiosensitization in most models, although with marked variability not explained by indicators of Pol\u03b8 activity. To pinpoint molecular determinants of radiosensitization by Pol\u03b8i, we performed a CRISPR knockout screen which revealed loss of the TP53BP1\/Shieldin pathway component\n                    <jats:italic toggle=\"yes\">SHLD2<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">FAM35A<\/jats:italic>\n                    ) as a vulnerability to Pol\u03b8i combined with RT. We found that\n                    <jats:italic toggle=\"yes\">SHLD2<\/jats:italic>\n                    is deleted in a subset of human prostate cancers, frequently alongside\n                    <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                    loss, an adverse prognostic factor. We demonstrated that\n                    <jats:italic toggle=\"yes\">SHLD2<\/jats:italic>\n                    loss not only increases sensitivity to RT alone, as reported previously, but also enhances the radiosensitizing effect of Pol\u03b8i, independently of\n                    <jats:italic toggle=\"yes\">PTEN<\/jats:italic>\n                    status and without requiring HR deficiency. Moreover, our findings support a model in which\n                    <jats:italic toggle=\"yes\">SHLD2<\/jats:italic>\n                    deficiency increases Pol\u03b8 dependence following RT, with Pol\u03b8 activity limiting DSB accumulation and chromosomal instability, via a compensatory mechanism independent of canonical MRE11\/CtIP-mediated DNA end resection. In summary, we found that\n                    <jats:italic toggle=\"yes\">SHLD2<\/jats:italic>\n                    loss is a collateral vulnerability that can be exploited through combined treatment with Pol\u03b8i and RT.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb4508","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T17:58:47Z","timestamp":1781287127000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["<i>SHLD2<\/i>\n                    loss is a synthetic vulnerability to Pol\u03b8 inhibition combined with radiotherapy"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1613-0291","authenticated-orcid":true,"given":"Gonzalo","family":"Rodriguez-Berriguete","sequence":"first","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, 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University of Oxford, Oxford, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1899-7323","authenticated-orcid":true,"given":"Marie Laure","family":"Boursier","sequence":"additional","affiliation":[{"name":"Artios Pharma, Babraham Research Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurora","family":"Cerutti","sequence":"additional","affiliation":[{"name":"Artios Pharma, Babraham Research Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Grinkevich","sequence":"additional","affiliation":[{"name":"Artios Pharma, Babraham Research Campus, Cambridge, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany Rebekah","family":"Hill","sequence":"additional","affiliation":[{"name":"Artios Pharma, Babraham Research Campus, Cambridge, 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