Daclatasvir, an antiviral drug, downregulates Tribbles 2 pseudokinase and re-sensitizes enzalutamide resistant prostate cancer cells.

FDA-approved enzalutamide is commonly prescribed to reduce growth of advanced prostate cancer by blocking androgen receptor function. However, enzalutamide-resistant prostate cancer (ERPC) invariably develops which progresses to metastatic, lethal disease. Management of ERPC poses special problem not only because available therapeutic regimens cannot effectively kill ERPC cells but also due to their propensity to invade large bones. Moreover, molecular mechanism(s) behind enzalutamide-resistance is not properly understood, which is delaying development of newer agents. We found that the pseudokinase, Tribbles 2 (TRIB2), is overexpressed in enzalutamide-resistant prostate cancer cells and plays critical role in their survival. Forced overexpression of TRIB2 enhances prostate cancer cell growth and confers resistance to physiological doses of enzalutamide, suggesting that TRIB2 plays an important role in the development and progression of ERPC. Though TRIB2 has emerged as an excellent molecular target for ERPC, suitable inhibitors are not commercially available for effective targeting. By designing a luciferase-tagged TRIB2 fusion protein-based assay system, we screened a library of about 1,600 compounds and found that daclatasvir (DCV), an antiviral drug, effectively inhibits TRIB2-luciferase. We also found that DCV degrades TRIB2 proteins by direct binding and re-sensitizes ERPC cells to enzalutamide treatment. Moreover, DCV at lower, sub-lethal doses synergize with enzalutamide to decrease the viability and induce apoptosis in prostate cancer cells. Since DCV is already approved by the FDA and well-tolerated in humans, based on our findings it appears that DCV is a promising, new agent for development of an effective therapy for advanced, enzalutamide-resistant, lethal prostate cancer.