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Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT\u2009&gt;\u2009TLK1\u2009&gt;\u2009NEK1\u2009&gt;\u2009ATR\u2009&gt;\u2009Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen\u2010independent (AI) colonies of LNCaP and TRAMP\u2010C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells <jats:italic>in vitro<\/jats:italic> (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long\u2010term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth <jats:italic>via<\/jats:italic> bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1\u2010T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1\/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT).<\/jats:p>","DOI":"10.1002\/ijc.32200","type":"journal-article","created":{"date-parts":[[2019,2,9]],"date-time":"2019-02-09T08:05:31Z","timestamp":1549699531000},"page":"1055-1067","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Targeting the TLK1\/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors"],"prefix":"10.1002","volume":"145","author":[{"given":"Vibha","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Louisiana State University Health Sciences Center  Shreveport LA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen Kumar","family":"Jaiswal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology 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