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Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth\/survival by recruitment of the TIP60\/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.<\/jats:p>","DOI":"10.64898\/2026.05.05.723058","type":"posted-content","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T11:55:14Z","timestamp":1778241314000},"source":"Crossref","is-referenced-by-count":0,"title":["MYC pathway reprogramming through a TIP60 coactivator switch in neuroendocrine lineage transition in prostate cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-1925","authenticated-orcid":false,"given":"Zhen","family":"Sun","sequence":"first","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy L.","family":"Zhao","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"SystImmune Inc., Princeton, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra F.","family":"Khan","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wazim M.","family":"Ismail","sequence":"additional","affiliation":[{"name":"Division of Experimental Pathology, Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teng","family":"Han","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhiksha","family":"Nandakumar","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serina","family":"Young","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lange","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Koche","sequence":"additional","affiliation":[{"name":"Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaus","family":"Schultz","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8528-5575","authenticated-orcid":false,"given":"Alexandre","family":"Gaspar-Maia","sequence":"additional","affiliation":[{"name":"Division of Experimental Pathology, Department of Lab Medicine and Pathology, Mayo Clinic, Rochester, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4955-6475","authenticated-orcid":false,"given":"Charles L.","family":"Sawyers","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA"},{"name":"Howard Hughes Medical Institute, Chevy Chase, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052521201038000_2026.05.05.723058v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0340-z"},{"key":"2026052521201038000_2026.05.05.723058v1.2","first-page":"201","article-title":"RB1","volume":"6","year":"2022","journal-title":"Cancer Lineage Plasticity, and Therapeutic Resistance. 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