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

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.