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However, most patients eventually develop acquired resistance. Here, we report that JPI-547, a second-generation PARP inhibitor targeting both PARP1\/2 and tankyrase, demonstrates potent antitumor activity in olaparib-sensitive and resistant BRCA1\/2 mutant models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Olaparib-resistant (OR) models were generated using BRCA-mutated human ovarian and breast cancer cell lines and ovarian Patient-Derived Tumor Xenograft (PDTX) by exposing to olaparib. For clinical relevance, public mRNA microarray datasets of ovarian and breast cancer were analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>JPI-547 demonstrated better antitumor efficacy in both olaparib-sensitive and resistant BRCA-mutated preclinical models than first-generation PARP inhibitors. Mechanistically, the on-target inhibition of PARP1\/2 and tankyrase by JPI-547 strongly inhibited the restoration of homologous recombination (HR) activity by suppressing RAD51 expression. This action resulted in the retardation of tumor growth in olaparib-sensitive and resistant ovarian PDTX models. Furthermore, high RAD51 expression was significantly associated with poor prognosis in ovarian and breast cancer patients based on public mRNA expression data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These results suggest the scientific rationale for further clinical development of JPI-547 for treating both PARP inhibitor-sensitive patients and those resistant to first-generation PARP inhibitors in BRCA-mutated cancers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1038\/s41416-026-03411-3","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T12:40:41Z","timestamp":1778071241000},"page":"503-517","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["JPI-547, a novel dual inhibitor of PARP1\/2 and tankyrase is more effective than first-generation PARP inhibitors in preclinical BRCA1\/2-mutated cancer models"],"prefix":"10.1038","volume":"135","author":[{"given":"Min Sil","family":"Kang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nar Bahadur","family":"Katuwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mithun","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa Deok","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong Gyu","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Min","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Hoen","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seul-Gi","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung Ryeol","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7943-974X","authenticated-orcid":false,"given":"Yong Wha","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"3411_CR1","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1038\/sj.onc.1203269","volume":"19","author":"CX Deng","year":"2000","unstructured":"Deng CX, Scott F. 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