Abstract 4650: Effect of prescription CYP3A inducers and inhibitors on response to anti-androgen therapy in prostate cancer

Abstract

Abstract Purpose: Prostate cancer affects elderly men who typically have multiple comorbidities requiring concomitant prescription medications, many of which are CYP inducers or inhibitors. Androgen deprivation therapy (ADT) is the mainstay therapy for treating advanced prostate cancer. Recently we demonstrated that CYP3A5 facilitates the nuclear translocation of androgen receptor (AR), promoting prostate cancer growth. As the mechanisms by which intratumoral CYP3A5 regulates AR in prostate cancer are not well understood, the clinical impact of concomitant drugs on the efficacy of ADT is presently unknown. This work describes a platform for assessing the effects of commonly prescribed drugs known to be CYP3A5 inducers or inhibitors on AR signaling and prostate cancer growth. Methods: We have created a lentiviral LNCaP based reporter system for monitoring changes in AR signaling utilizing a construct comprising a promotor containing AR inducible transcriptional response elements (TREs), fused with firefly luciferase, whereas the negative control (NC) lacks the TREs. We used both a mixed transfected pool and individually selected clones to monitor changes in AR activity. Results: We tested our assay system by inhibiting CYP3A5 gene expression in LNCaP cells using siRNA and then treating it with DHT. Our data indicate that CYP3A5 siRNA reduced DHT induced AR activity significantly as compared to non-target (NT) siRNA. We further tested our reporter system with rifampicin, phenytoin (both CYP3A inducers) and ritonavir, fluoxetine, amiodarone (CYP3A inhibitors). Rifampicin (antibiotic) and phenytoin (anticonvulsant) showed significant (P≤0.05) induction of AR activity as shown by increased luminescence units. Out of the three inhibitors which were tested amiodarone (antiarrhythmic) and ritonavir (antiretroviral) reduced the AR activity by 50% and 80% respectively whereas fluoxetine (antidepressant) did not result in any significant changes. Both amiodarone and ritonavir also inhibited R1881 (artificial androgen) induced AR activity as compared to control. Conclusion: Concomitant medications can alter the AR activity thus modifying the response to ADT therapy in prostate cancer patients. These finding support the notion that an CYP3A inhibitor-rich concomitant medical regimen may provide additional clinical benefit for men undergoing ADT and further support the concept of targeting nuclear translocation as a therapeutic adjunct in ADT. Citation Format: Ranjana Mitra, Oscar B. Goodman Jr. Effect of prescription CYP3A inducers and inhibitors on response to anti-androgen therapy in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4650.