Abstract B017: Role of CYP3A5 in modulating androgen receptor signaling and its relevance in African American prostate cancer patients

Abstract

Abstract Introduction: African-American men (AA) often present with aggressive castration-resistant prostate cancer (CRPC), due to highly active androgen receptor (AR). AR is a ligand-activated transcription factor that promotes expression of genes responsible for cell proliferation and growth. Previously, we have shown that CYP3A5 promotes AR nuclear translocation and activation leading to increased prostate cancer (PC) growth. 73% of AAs carrying wild-type CYP3A5 (*1/*1) express full-length functional CYP3A5, whereas 95% of Caucasians carry mutant (*3/*3) variant producing truncated nonfunctional protein. Difference in CYP3A5 expression leads to highly active AR and aggressive disease in AAs. Additionally, most of the PC patients are prescribed concomitant medications to manage age-related comorbidities. Many of these drugs are known modulators of CYP3A5; modulation of CYP3A5 may alter efficacy of ADT in these patients. Our work is focused on characterizing the effect of CYP3A5 modulating drugs on AR signaling in AAs. Methods: q-RT-PCR based profiler assay was used to study effect of CYP3A5 modulation on AR-regulated genes using cDNA from nontarget (NT) and CYP3A5 siRNA treated cells. Confocal microscopy and cell fractionation assays were performed to evaluate and confirm the effect of CYP3A5 modulating drugs on AR nuclear translocation. Genes shortlisted from q-PCR based profiler assays were analyzed for change of expression in response to CYP3A5 modulating drugs. MDAPCA2b (AA origin, *1/*3) and LNCaP (Caucasian, *3/*3) cell lines were used for above experiments. Results: CYP3A5 siRNA pool treatment downregulates AR regulated genes identified using q-PCR based profiler assay, performed with cDNA from CYP3A5 siRNA pool and NT treated MDAPCA2b cells. These downregulated genes include SCL45A3, FKBP5, NCAPD3, MYC, MME, ELL2, PIK3R3, HPRT1 and SPDEF with p-value of ≤0.005. These genes are known to regulate AR nuclear translocation, cell cycle progression, and cell growth. CYP3A5 siRNA treated MDACPA2b/ LNCaP cells showed decreased AR nuclear translocation and PSA production. Commonly prescribed drugs that are either CYP inhibitors (amiodarone, ritonavir) or inducers (phenytoin, rifampicin) were tested for their ability to alter AR signaling. The results show that the CYP inducers promoted AR nuclear migration and downstream signaling whereas CYP3A5 inhibitors blocked it. Further, CYP3A5 siRNA treated MDAPCa2b cells do not show any increase in AR nuclear migration with phenytoin treatment (CYP3A inducer), confirming that the activation of AR activity is specific to changes in CYP3A5 activity. Conclusions: Concomitantly prescribed CYP3A5 modulating drugs can alter downstream AR signaling, cell growth, and ADT efficacy in men, more so in AAs expressing wild-type CYP3A5. We propose to further characterize drug-induced CYP3A5 modulation of AR signaling to develop a guideline for physicians coprescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT. Citation Format: Priyatham Gorjala, Oscar B. Goodman Jr, Ranjana Mitra. Role of CYP3A5 in modulating androgen receptor signaling and its relevance in African American prostate cancer patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B017.