{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:11:58Z","timestamp":1793427118931,"version":"4.5.0"},"reference-count":57,"publisher":"National Academy of Sciences","issue":"5","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"DOD | MHS | Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["HT94252310910"],"award-info":[{"award-number":["HT94252310910"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | NIH","doi-asserted-by":"publisher","award":["5P01CA163227"],"award-info":[{"award-number":["5P01CA163227"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:p>Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)\u2013proficient tumors. To investigate this discrepancy between preclinical and clinical results, we profiled the effects of PARP inhibition in prostate cancer models in the presence or absence of AR inhibition. Surprisingly, AR inhibition impaired response to PARP inhibitors in castration-sensitive cells and had no effect on response in castration-resistant cells. AR inhibition also did not regulate DNA repair in either the castration-resistant or castration-sensitive setting. Instead, we find that cell cycle progression is required for response to PARP inhibition in homologous recombination\u2013proficient prostate cancer.<\/jats:p>","DOI":"10.1073\/pnas.2515790122","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T17:44:56Z","timestamp":1769535896000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination\u2013proficient prostate cancer"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2223-5022","authenticated-orcid":false,"given":"Nicole A.","family":"Traphagen","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esm\u00e9","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara","family":"Akhshi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7880-8593","authenticated-orcid":false,"given":"Ramya","family":"Ravindranathan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0931-6775","authenticated-orcid":false,"given":"Christian","family":"Alfieri","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Lu","sequence":"additional","affiliation":[{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buraq","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2617-7499","authenticated-orcid":false,"given":"Alok K.","family":"Tewari","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4546-7371","authenticated-orcid":false,"given":"Steven P.","family":"Balk","sequence":"additional","affiliation":[{"name":"Department of Medicine, Beth Israel Deaconess Medical Center","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Division of Human Biology, Fred Hutchinson Cancer Research Center","place":["Seattle"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-3807","authenticated-orcid":false,"given":"Eva","family":"Corey","sequence":"additional","affiliation":[{"name":"Department of Urology, University of Washington","place":["Seattle"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]},{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6168-6294","authenticated-orcid":false,"given":"Alan D.","family":"D\u2019Andrea","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]},{"name":"Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xintao","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]},{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8213-1658","authenticated-orcid":false,"given":"Myles","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School","place":["Boston"]},{"name":"Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0108"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aam7479"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4848-x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(23)00382-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02704-x"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.06.009"},{"key":"e_1_3_4_7_2","first-page":"6","article-title":"ODAC marathon: Committee charges through a pileup of clinical questions in a two-day, four-application session","volume":"51","author":"Cobb J.","year":"2025","unstructured":"J. Cobb, ODAC marathon: Committee charges through a pileup of clinical questions in a two-day, four-application session. Cancer Lett. 51, 6\u201327 (2025).","journal-title":"Cancer Lett."},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M202390200"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705989200"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1149250"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.023879"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.08.014"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908547116"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.01.008"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1127196"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.11.017"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.02.034"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0172"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24798"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3010563"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.02759"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30906-3"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127613"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41391-022-00636-0"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-0488"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2013.08.011"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2753"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2782"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24630"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/pros.23313"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-4289"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2975"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01012"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c02276"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01725"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-0301"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-22-0423"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-2094"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-023-02687-0"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-23-0358"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.09.064"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.1427.3.11"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm049354h"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.32.20213"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.21.1869"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03443"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03445"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07217-2"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.07.015"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2139-9"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1621"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts356"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gpb.2020.11.007"},{"key":"e_1_3_4_56_2","doi-asserted-by":"crossref","unstructured":"N. A. Traphagen M. Brown Lack of synergy between AR targeted therapies and PARP inhibition in homologous recombination- proficient prostate cancer. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE315878. Deposited 7 January 2026.","DOI":"10.1101\/2025.06.02.657429"},{"key":"e_1_3_4_57_2","doi-asserted-by":"crossref","unstructured":"N. A. Traphagen M. Brown Lack of synergy between AR targeted therapies and PARP inhibition in homologous recombination- proficient prostate cancer. Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE315883. Deposited 7 January 2026.","DOI":"10.1101\/2025.06.02.657429"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2515790122","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2515790122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T17:45:04Z","timestamp":1769535904000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2515790122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":57,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,2,3]]}},"alternative-id":["10.1073\/pnas.2515790122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2515790122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"2025-06-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2515790122"}}