Nalairndran, Geetha and Chung, Ivy and Abdul Razack, Azad Hassan Abdul and Chung, Felicia Fei-Lei and Hii, Ling-Wei and Lim, Wei-Meng and Looi, Chin King and Mai, Chun-Wai and Leong, Chee-Onn (2021) Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells. Journal of Cellular and Molecular Medicine, 25 (17). pp. 8187-8200. ISSN 1582-1838, DOI https://doi.org/10.1111/jcmm.16684.
Full text not available from this repository.Abstract
Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting 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-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific 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.
| Item Type: | Article |
|---|---|
| Funders: | Ministry of Education, Malaysia[ERGS/1/2013/SKK01/IMU/02/1], Ministry of Education, Malaysia[FRGS/1/2016/SKK08/IMU/01/1] |
| Uncontrolled Keywords: | Baricitinib;JAK1;Prostate cancer;RNAi screen;Ruxolitinib |
| Subjects: | R Medicine R Medicine > RC Internal medicine R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 16 Jun 2022 07:58 |
| Last Modified: | 16 Jun 2022 07:58 |
| URI: | http://eprints.um.edu.my/id/eprint/34234 |
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