{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:21:07Z","timestamp":1780392067505,"version":"3.54.1"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T00:00:00Z","timestamp":1765238400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Prostate"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metastatic prostate cancers are primarily treated by therapies targeting the androgen\/androgen receptor (AR) signaling pathways. Despite the initial success, treatment resistance is almost universal, leading to disease progression and patient mortality. Currently, the molecular mechanism and vulnerability of treatment\u2010resistant prostate cancers are poorly understood. These knowledge gaps are major obstacles in improving treatment and patient survival. Recently, we used the single\u2010cell approach to establish a new anti\u2010androgen\/AR resistant cell model, in which tumor cells had an AR\u2010low phenotype, expressing low levels of AR and AR\u2010target genes, and were resistant to androgen\u2010deprivation (ADT) and enzalutamide in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We determined the transcriptome of the treatment\u2010resistant AR\u2010low cells with bulk RNA\u2010Seq, qRT\u2010PCR, and chromatin immunoprecipitation (ChIP)\u2010qPCR. We identified a metabolic vulnerability of the resistant cells with siRNA, plasmid\u2010based overexpression and metabolic assays. We next determined whether the vulnerability can be exploited by small molecule inhibitors to enhance enzalutamide with proliferation and colony formation assays and Incucyte\u2010based live cell imaging. We also determined the clinical relevance of the vulnerability with the prostate cancer TCGA data set.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The AR\u2010low treatment resistant tumor cells had significantly different transcriptomes from the treatment\u2010sensitive counterparts, notably represented by the EMT\u2010high expression phenotype. The resistant cells were deficient in the expression of NAPRT, a rate determining enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis, causing the resistant cells to be vulnerable to NAD+ biosynthesis inhibitors. Importantly, this vulnerability can be exploited to enhance enzalutamide efficacy in the castration sensitive setting as NAPRT\u2010low was phenotypically associated with EMT\u2010high and AR\u2010low in subpopulations of tumor cells and patient samples.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our newly established treatment\u2010resistant cell model has the AR\u2010low\/EMT\u2010high phenotype, which is clinically associated with enzalutamide resistance in patients. NAPRT\u2010deficiency (NAPRT\u2010low) can be a novel vulnerability associated with the AR\u2010low\/EMT\u2010high phenotype and thus can be targeted by NAD+ inhibitors to improve enzalutamide efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/pros.70100","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T04:49:11Z","timestamp":1765342151000},"page":"428-439","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Prostate Cancer Cells With the AR\u2010Low and EMT\u2010High Phenotype Are Vulnerable to NAD+ Synthesis Inhibitors"],"prefix":"10.1002","volume":"86","author":[{"given":"Hyun\u2010Kyung","family":"Ko","sequence":"first","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Foertsch","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasen","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan\u00e9t","family":"Pittsenbarger","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changhui","family":"Xue","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyo","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Geng","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9382-0419","authenticated-orcid":false,"given":"Lina","family":"Gao","sequence":"additional","affiliation":[{"name":"Biostatistics Core, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Z.","family":"Qian","sequence":"additional","affiliation":[{"name":"Division of Oncological Sciences, Knight Cancer Institute Oregon Health &amp; Science University Portland Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,9]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3678"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc801"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-18-0289"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1405095"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2014.72"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc4016"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.06.028"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08671-2"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36439-7"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0040-3"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2014.00370"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110595"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrurol.2018.22"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922207117"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-21-0002"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0815-5"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI128212"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx283"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30336"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-0594"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-00313-x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202113943"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.00656"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0692-5"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-3079"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1150-2"},{"key":"e_1_2_8_28_1","doi-asserted-by":"crossref","unstructured":"A.Kim P.Bhardwaj C. 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