Triphenyl phosphate promotes PXR-associated, MEN1-dependent exposure-conditioned enzalutamide tolerance in prostate cancer.

Androgen receptor pathway inhibitors (ARPIs) prolong survival in prostate cancer, yet durable control is frequently lost through transcriptional adaptation and lineage plasticity. Whether environmental endocrine-disrupting chemicals can actively bias this trajectory and create tractable resistance dependencies remains unclear. Here we show that chronic low-dose exposure to triphenyl phosphate (TPP) induces exposure-conditioned, partially persistent and reversible enzalutamide tolerance in AR-positive prostate cancer cells, accompanied by increased colony formation. Tolerance persists initially after exposure withdrawal but declines during washout, and TPP rechallenge increases GR50 again. A pooled CRISPR screen across two genetic backgrounds converged on MEN1 as the most robust concordant hit, and genetic perturbation and rescue identified a MEN1 dependency that was most apparent in the TPP-conditioned tolerant state. Mechanistically, TPP induced NR1I2 and MEN1 mRNA, endogenous target genes, and PXR-associated reporter activity; antagonist-sensitive transcriptional responses, SPA70-mediated reversal of tolerance, and MEN1-locus regulatory-region visualization were consistent with engagement of a PXR/NR1I2-associated receptor program. Targeted chromatin profiling identified MEN1-dependent changes in H3K4me3, H3K27ac and accessibility at selected AR and plasticity-associated loci. TPP_long reduced H3K4me3 and accessibility at AR loci, while MEN1 CRISPRi opposed the major transcriptional and chromatin changes. In LNCaP-luc xenografts, TPP exposure attenuated enzalutamide-mediated tumor suppression, and MEN1 CRISPRi reduced tumor burden in the TPP + enzalutamide background. This reduction in enzalutamide control was not reproduced in the exploratory VCaP model under androgen deprivation. Together, these data support an exposure-conditioned receptor-to-chromatin model in which MEN1 supports an AR-low/plasticity-high adaptive state.