{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:14:00Z","timestamp":1789924440485,"version":"4.0.1"},"reference-count":51,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K18610"],"award-info":[{"award-number":["19K18610"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K09345"],"award-info":[{"award-number":["21K09345"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["24K12482"],"award-info":[{"award-number":["24K12482"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Despite advances in androgen receptor signaling inhibitors (ARSIs) and poly (ADP\u2010ribose) polymerase inhibitors (PARPIs), metastatic castration\u2010resistant prostate cancer (mCRPC) remains lethal. PARPIs clinical efficacy is limited in patients with homologous recombination repair deficiencies, such as\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    mutations, due to resistance. Thus, identifying novel synthetic lethal interactions with PARP may expand treatment options and improve therapeutic efficacy. Here, to identify genes that influence sensitivity to the PARPI olaparib, we conducted a genome\u2010wide CRISPR\u2010Cas9 knockout screening of 18,010 genes in DU145, 22Rv1, and LNCaP prostate cancer cell lines. Our screening identified PARP and LIG1 as synthetic lethality\u2010inducing factors, whereas TP53 conferred resistance to PARPIs. Simultaneous inhibition of LIG1 and PARP increased DNA damage and apoptosis. Additionally, the combination of the LIG1 inhibitor L82\u2010G17 with olaparib exhibited synergistic effects. To the best of our knowledge, we validated this combination therapy in\u00a0vivo for the first time, suppressing tumor growth in a DU145 xenograft model while minimizing toxicity in normal tissues. Immunohistochemical analysis revealed that LIG1 was overexpressed in CRPC tissues, suggesting its potential as a therapeutic target. This study established LIG1 as a novel synthetic lethality\u2010inducing factor in prostate cancer, showing that L82\u2010G17 enhances the efficacy of olaparib, regardless of the\n                    <jats:italic>BRCA<\/jats:italic>\n                    mutation status. These findings suggest that the combination of PARP and LIG1 inhibitors could be a novel therapeutic strategy for mCRPC.\n                  <\/jats:p>","DOI":"10.1111\/cas.70194","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T01:39:29Z","timestamp":1758073169000},"page":"3403-3416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Development of a Synthetic Lethality\u2010Based Combination Therapy Using\n                    <scp>LIG1<\/scp>\n                    and\n                    <scp>PARP<\/scp>\n                    Inhibitors for Prostate Cancer"],"prefix":"10.1111","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3079-0520","authenticated-orcid":false,"given":"Masaru","family":"Tani","sequence":"first","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita 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The University of Osaka Graduate School of Medicine  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunsuke","family":"Inoguchi","sequence":"additional","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Horibe","sequence":"additional","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita 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Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9369-4264","authenticated-orcid":false,"given":"Atsunari","family":"Kawashima","sequence":"additional","affiliation":[{"name":"Department of Urology The University of Osaka Graduate School of Medicine  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences The University of Osaka  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Obika","sequence":"additional","affiliation":[{"name":"Graduate School of Pharmaceutical Sciences The University of Osaka  Suita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Yusa","sequence":"additional","affiliation":[{"name":"Stem Cell Genetics, Institute for Frontier Life and Medical Sciences Kyoto University  Kyoto 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Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70194","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T10:26:16Z","timestamp":1764584776000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,16]]},"references-count":51,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/cas.70194"],"URL":"https:\/\/doi.org\/10.1111\/cas.70194","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,16]]},"assertion":[{"value":"2025-04-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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