Gut microbial metabolism of Flutamide attenuates its therapeutic efficacy against prostate cancer

Endocrine drugs serve as the cornerstone of prostate cancer treatment. Flutamide, a representative first-generation antiandrogen, has been relegated to the treatment of recurrent prostate cancer due to novel drug development and therapeutic resistance. Our study shows the gut microbiota contributes to this resistance. Specifically, gut bacteria metabolize Flutamide into FLU-6 (a nitroreduction product) and FLU-9 (an acetylation product), involving species like Escherichia coli. Gene knockout revealed E. coli nfsA and nfsB as essential for Flutamide nitroreduction, while heterologous expression confirmed acetyltransferases mediate the production of acetylated metabolites. In the antibiotic-treated mouse model, antibiotic intervention significantly reduced microbial metabolites of Flutamide. In addition, FLU-6 was further metabolized by the host into FLU-5. Synthesized FLU-6, FLU-9, and FLU-5 showed no anticancer activity in prostate cancer cell lines. In a xenograft model, oral administration of E. coli diminished Flutamide's efficacy by altering its metabolic profile. Clinical sample analysis revealed substantial interpatient variability, and patients could be categorized into subgroups with high or low metabolic capability. These findings provide new insights into personalized prostate cancer therapy, highlight the role of the gut microbiota in Flutamide response and suggest a strategy for optimizing antiandrogen treatments.