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Abiraterone, Enzalutamide, or Apalutamide. Initially, this therapy is highly effective, but a significant challenge arises as most patients eventually develop resistance, resulting in castration-resistant prostate cancer (CRPC). Furthermore, the sequential use of these drugs can lead to cross-resistance, diminishing their efficacy. Tumor heterogeneity plays a pivotal role in the development of resistance to different treatments. This study utilized cellular models of CRPC to assess the response to Apalutamide when it was administered as a second- or third-line treatment. Functional and genetic analyses were conducted in various CRPC cell models exposed to Apalutamide. These analyses included real-time cell monitoring assays, flow cytometry, clonogenicity assays, and RT-qPCR. CRPC cell models were capable of continued proliferation, maintained cell cycle profiles similar to those of untreated cells, and retained their clonogenic potential. Cross-resistance to Apalutamide in models of ADT, ADT plus Enzalutamide, or Abiraterone resistance did not correlate with the expression levels of AR-V7 and AR-V9 variants. Gene expression analysis of resistant prostate cancer cell lines revealed that treatment with Apalutamide induced the emergence of more aggressive phenotypes, including cancer stem cells or neuroendocrine differentiation profiles. Most CRPC cell models developed cross-resistance to Apalutamide and were able to proliferate and retain their clonogenic capability. Apalutamide resistance was not linked to the expression of AR-V7 or AR-V9 variants but was instead associated to bypass of AR signaling pathway and the emergence of more aggressive expression profiles.<\/jats:p>","DOI":"10.3390\/ijms26135939","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T08:13:56Z","timestamp":1750407236000},"page":"5939","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Phenotypic Plasticity and Androgen Receptor Bypass Drive Cross-Resistance to Apalutamide in Castration-Resistant Prostate Cancer Cell Models"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9654-2098","authenticated-orcid":false,"given":"Iris","family":"Simon","sequence":"first","affiliation":[{"name":"Gene Regulation, Stem Cells and Development Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Avenida Fuentenueva s\/n, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-5132","authenticated-orcid":false,"given":"Jose Manuel","family":"Sanchez-Manas","sequence":"additional","affiliation":[{"name":"Gene Regulation, Stem Cells and Development Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Avenida Fuentenueva s\/n, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Perales","sequence":"additional","affiliation":[{"name":"Gene Regulation, Stem Cells and Development Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Avenida Fuentenueva s\/n, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Martinez-Navajas","sequence":"additional","affiliation":[{"name":"Gene Regulation, Stem Cells and Development Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Avenida Fuentenueva s\/n, 18071 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0304-221X","authenticated-orcid":false,"given":"Jorge","family":"Ceron-Hernandez","sequence":"additional","affiliation":[{"name":"Gene Regulation, Stem Cells and Development Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Avenida Fuentenueva s\/n, 18071 Granada, Spain"},{"name":"Liquid Biopsies and Cancer Interception Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7968-5353","authenticated-orcid":false,"given":"Pedro J.","family":"Real","sequence":"additional","affiliation":[{"name":"Gene Regulation, Stem Cells and Development Group, GENyO, Pfizer-University of Granada-Andalusian Regional Government Centre for Genomics and Oncological Research, Avenida de la Ilustracion 114, PTS Granada, 18016 Granada, Spain"},{"name":"Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, Avenida Fuentenueva s\/n, 18071 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. 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