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Androgen receptor (AR) inhibitors represent the mainstay of prostate cancer treatment. In a genome-wide CRISPR-Cas9 screen using LNCaP prostate cancer cells, loss of co-repressor  TLE3  conferred resistance to AR antagonists apalutamide and enzalutamide. Genes differentially expressed upon  TLE3  loss share AR as the top transcriptional regulator, and  TLE3  loss rescued the expression of a subset of androgen-responsive genes upon enzalutamide treatment. GR expression was strongly upregulated upon AR inhibition in a  TLE3 -negative background. This was consistent with binding of TLE3 and AR at the  GR  locus. Furthermore, GR binding was observed proximal to TLE3/AR-shared genes. GR inhibition resensitized  TLE3  KO  cells to enzalutamide. Analyses of patient samples revealed an association between TLE3 and GR levels that reflected our findings in LNCaP cells, of which the clinical relevance is yet to be determined. Together, our findings reveal a mechanistic link between TLE3 and GR-mediated resistance to AR inhibitors in human prostate cancer.

TLE3 loss confers AR inhibitor resistance by facilitating GR-mediated human prostate cancer cell growth