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U.S.A."],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:p>\n                    Intrinsic and acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) remains a major barrier in treating homologous recombination (HR) repair-deficient tumors, including those with germline or somatic\n                    <jats:italic toggle=\"yes\">BRCA1\/2<\/jats:italic>\n                    mutations. Although PARPi are FDA approved for adjuvant treatment of locally advanced or metastatic breast cancer in patients with germline\n                    <jats:italic toggle=\"yes\">BRCA1\/2<\/jats:italic>\n                    mutations, emerging data support their use as monotherapy in the neoadjuvant setting. Promising safety profiles of newer-generation PARPi further support this potential. However, resistance mechanisms specific to the neoadjuvant setting are poorly understood. To address this gap, we leveraged resources from a phase II neoadjuvant clinical trial (NCT03499353), analyzing tumors from patients with germline\n                    <jats:italic toggle=\"yes\">BRCA1\/2<\/jats:italic>\n                    mutant breast tumors before and after six months of talazoparib monotherapy. Whole-transcriptome analyses were performed on these samples. Additionally, we established orthotopic patient-derived xenograft models from a subset of the patient tumors and conducted whole-exome and whole-transcriptome analysis. This integrative approach revealed both known and previously unknown PARPi resistance mechanisms. In one case, overexpression of\n                    <jats:italic toggle=\"yes\">BRN2<\/jats:italic>\n                    , encoding a transcription factor that plays a critical role in neurogenesis, led to activation of ATR\/RAD51 and STAT3 pathways, restoring HR repair. BRN2-driven resistance could be reversed with ATR and STAT3 inhibitors, resensitizing cells to talazoparib. In another, an HR repair proficient tumor subclone lacking Shieldin 2 expression expanded during treatment and accounted for intrinsic resistance. Our findings highlight the need to determine intrinsic and anticipate acquired resistance pathways in treatment-na\u00efve tumors and support combining PARPi with targeted agents to improve outcomes in the neoadjuvant setting.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2513742123","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T17:36:01Z","timestamp":1775842561000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Resistance to neoadjuvant talazoparib in triple-negative breast cancer by BRN2-induced ATR\/STAT3 pathways or SHLD2 subclone expansion"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0189-3069","authenticated-orcid":false,"given":"Noor M.","family":"Abdulkareem","sequence":"first","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer 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