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Docetaxel\u2010based therapy remains the first\u2010line treatment for metastatic castration\u2010resistant prostate cancer. However, dose\u2010limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high\u2010throughput kinome\u2010wide loss\u2010of\u2010function screen. Further drug\u2010gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA\u2010approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel\u2010induced apoptosis in PCa cells. Furthermore, inhibition of JAK1\/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)\u2013negative DU145 and PC3 cells, but not in the AR\u2010positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2\u2010specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.<\/jats:p>","DOI":"10.1111\/jcmm.16684","type":"journal-article","created":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T06:42:48Z","timestamp":1627540968000},"page":"8187-8200","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells"],"prefix":"10.1111","volume":"25","author":[{"given":"Geetha","family":"Nalairndran","sequence":"first","affiliation":[{"name":"Department of Pharmacology Faculty of Medicine University of Malaya  Kuala Lumpur Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-8123","authenticated-orcid":false,"given":"Ivy","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of 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