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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,4,25]]},"abstract":"<jats:p>Prostate cancer (PC) is the most frequently diagnosed malignancy and a leading cause of cancer deaths in US men. Many PC cases metastasize and develop resistance to systemic hormonal therapy, a stage known as castration-resistant prostate cancer (CRPC). Therefore, there is an urgent need to develop effective therapeutic strategies for CRPC. Traditional drug discovery pipelines require significant time and capital input, which highlights a need for novel methods to evaluate the repositioning potential of existing drugs. Here, we present a computational framework to predict drug sensitivities of clinical CRPC tumors to various existing compounds and identify treatment options with high potential for clinical impact. We applied this method to a CRPC patient cohort and nominated drugs to combat resistance to hormonal therapies including abiraterone and enzalutamide. The utility of this method was demonstrated by nomination of multiple drugs that are currently undergoing clinical trials for CRPC. Additionally, this method identified the tetracycline derivative COL-3, for which we validated higher efficacy in an isogenic cell line model of enzalutamide-resistant vs. enzalutamide-sensitive CRPC. In enzalutamide-resistant CRPC cells, COL-3 displayed higher activity for inhibiting cell growth and migration, and for inducing G1-phase cell cycle arrest and apoptosis. Collectively, these findings demonstrate the utility of a computational framework for independent validation of drugs being tested in CRPC clinical trials, and for nominating drugs with enhanced biological activity in models of enzalutamide-resistant CRPC. The efficiency of this method relative to traditional drug development approaches indicates a high potential for accelerating drug development for CRPC.<\/jats:p>","DOI":"10.1073\/pnas.2218522120","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T15:11:55Z","timestamp":1681744315000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Computational drug discovery for castration-resistant prostate cancers through in vitro drug response modeling"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8978-8310","authenticated-orcid":false,"given":"Weijie","family":"Zhang","sequence":"first","affiliation":[{"name":"Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455"},{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8311-581X","authenticated-orcid":false,"given":"Adam M.","family":"Lee","sequence":"additional","affiliation":[{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sampreeti","family":"Jena","sequence":"additional","affiliation":[{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3973-4277","authenticated-orcid":false,"given":"Yingbo","family":"Huang","sequence":"additional","affiliation":[{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeung","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2932-3554","authenticated-orcid":false,"given":"Kiel T.","family":"Tietz","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3797-836X","authenticated-orcid":false,"given":"Conor R.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7277-031X","authenticated-orcid":false,"given":"Mei-Chi","family":"Su","sequence":"additional","affiliation":[{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Mentzer","sequence":"additional","affiliation":[{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander L.","family":"Ling","sequence":"additional","affiliation":[{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingming","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott M.","family":"Dehm","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, The University of Minnesota Medical School, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9862-0368","authenticated-orcid":false,"given":"R. Stephanie","family":"Huang","sequence":"additional","affiliation":[{"name":"Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, MN 55455"},{"name":"The Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","unstructured":"R. L. Siegel K. D. Miller H. E. Fuchs A. Jemal Cancer statistics 2022. CA 72 7\u201333 (2022) 10.3322\/caac.21708.","DOI":"10.3322\/caac.21708"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","unstructured":"M. Kirby C. Hirst E. D. Crawford Characterising the castration-resistant prostate cancer population: A systematic review. Int. J. Clin. 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Seashore-Ludlow Harnessing connectivity in a large-scale small-molecule sensitivity dataset. Cancer Discov. 5 1210\u20131223 (2015) 10.1158\/2159-8290.CD-15-0235.","DOI":"10.1158\/2159-8290.CD-15-0235"},{"key":"e_1_3_4_18_2","doi-asserted-by":"crossref","unstructured":"M. G. Rees Correlating chemical sensitivity and basal gene expression reveals mechanism of action. Nat. Chem. Biol. 12 109\u2013116 (2016) 10.1038\/nchembio.1986.","DOI":"10.1038\/nchembio.1986"},{"key":"e_1_3_4_19_2","doi-asserted-by":"crossref","unstructured":"R. J. Lee M. R. Smith Targeting MET and VEGFR signaling in castration-resistant prostate cancer. Cancer J. 19 90\u201398 (2013) 10.1097\/PPO.0b013e318281e280.","DOI":"10.1097\/PPO.0b013e318281e280"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","unstructured":"J. P. Droz Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel. 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Chu A phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomas. Invest. New Drugs. 25 359\u2013367 (2007) 10.1007\/s10637-006-9031-6.","DOI":"10.1007\/s10637-006-9031-6"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","unstructured":"P. M. Schnepp Single-cell transcriptomics analysis identifies nuclear protein 1 as a regulator of docetaxel resistance in prostate cancer cells. Mol. Cancer Res. 18 1290\u20131301 (2020) 10.1158\/1541-7786.MCR-20-0051.","DOI":"10.1158\/1541-7786.MCR-20-0051"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","unstructured":"D. P. Petrylak Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351 1513\u20131520 (2004) 10.1056\/NEJMoa041318.","DOI":"10.1056\/NEJMoa041318"},{"key":"e_1_3_4_30_2","doi-asserted-by":"crossref","unstructured":"Y. Shan GAS5 can be a biomarker for docetaxel response in castration resistant prostate cancer. Front. Oncol. 11 675215 (2021) https:\/\/www.frontiersin.org\/article\/10.3389\/fonc.2021.675215.","DOI":"10.3389\/fonc.2021.675215"},{"key":"e_1_3_4_31_2","doi-asserted-by":"crossref","unstructured":"Y. Khoshkar Mortality in men with castration-resistant prostate cancer\u2014A long-term follow-up of a population-based real-world cohort. BJUI Compass. 3 173\u2013183 (2022) 10.1002\/bco2.116.","DOI":"10.1002\/bco2.116"},{"key":"e_1_3_4_32_2","doi-asserted-by":"crossref","unstructured":"L. Dong R. C. Zieren W. Xue T. M. de Reijke K. J. Pienta Metastatic prostate cancer remains incurable why? Asian J. Urol. 6 26\u201341 (2019) 10.1016\/j.ajur.2018.11.005.","DOI":"10.1016\/j.ajur.2018.11.005"},{"key":"e_1_3_4_33_2","doi-asserted-by":"crossref","unstructured":"Genomics of Drug Sensitivity in Cancer (GDSC): A resource for therapeutic biomarker discovery in cancer cells | Nucleic Acids Research | Oxford Academic. https:\/\/academic.oup.com\/nar\/article\/41\/D1\/D955\/1059448. Accessed October 31 2021.","DOI":"10.1093\/nar\/gks1111"},{"key":"e_1_3_4_34_2","doi-asserted-by":"crossref","unstructured":"H. F. Bahmad Overcoming drug resistance in advanced prostate cancer by drug repurposing. Med. Sci. 10 15 (2022) 10.3390\/medsci10010015.","DOI":"10.3390\/medsci10010015"},{"key":"e_1_3_4_35_2","doi-asserted-by":"crossref","unstructured":"L. A. Carabet Computer-aided discovery of small molecules targeting the RNA splicing activity of hnRNP A1 in castration-resistant prostate cancer. 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Cancer Cell 32 474\u2013489.e6 (2017) 10.1016\/j.ccell.2017.09.003.","DOI":"10.1016\/j.ccell.2017.09.003"},{"key":"e_1_3_4_46_2","doi-asserted-by":"crossref","unstructured":"P. Corn F. Wang W. L. McKeehan N. Navon Targeting fibroblast growth factor pathways in prostate cancer. Clin. Cancer Res. 19 5856\u20135866 (2013) 10.1158\/1078-0432.CCR-13-1550.","DOI":"10.1158\/1078-0432.CCR-13-1550"},{"key":"e_1_3_4_47_2","doi-asserted-by":"crossref","unstructured":"C. Wang Z. Liu Y. Ke F. Wang Intrinsic FGFR2 and ectopic FGFR1 signaling in the prostate and prostate cancer. Front. Genet. 10 12 (2019) 10.3389\/fgene.2019.00012.","DOI":"10.3389\/fgene.2019.00012"},{"key":"e_1_3_4_48_2","doi-asserted-by":"crossref","unstructured":"J. Teishima Fibroblast growth factor family in the progression of prostate cancer. J. Clin. Med. 8 183 (2019) 10.3390\/jcm8020183.","DOI":"10.3390\/jcm8020183"},{"key":"e_1_3_4_49_2","doi-asserted-by":"crossref","unstructured":"R. F. da Silva Nintedanib inhibits growth of human prostate carcinoma cells by modulating both cell cycle and angiogenesis regulators. Sci. Rep. 8 9540 (2018) 10.1038\/s41598-018-27831-1.","DOI":"10.1038\/s41598-018-27831-1"},{"key":"e_1_3_4_50_2","doi-asserted-by":"crossref","unstructured":"S. Feng Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors. Oncotarget 8 6179\u20136192 10.2016.18632\/oncotarget.14049.","DOI":"10.18632\/oncotarget.14049"},{"key":"e_1_3_4_51_2","doi-asserted-by":"crossref","unstructured":"H. Hieronymus Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10 321\u2013330 (2006) 10.1016\/j.ccr.2006.09.005.","DOI":"10.1016\/j.ccr.2006.09.005"},{"key":"e_1_3_4_52_2","doi-asserted-by":"crossref","unstructured":"D. B. Solit H. I. Scher N. Rosen Hsp90 as a therapeutic target in prostate cancer. Semin. 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