Affiliations 

  • 1 Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 2 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 3 Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE), International Agency for Research on Cancer World Health Organization, Lyon CEDEX 08, France
  • 4 Center for Cancer and Stem Cell Research, Institute for Research, Development and Innovation (IRDI), International Medical University, Kuala Lumpur, Malaysia
J Cell Mol Med, 2021 Sep;25(17):8187-8200.
PMID: 34322995 DOI: 10.1111/jcmm.16684

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.