Abstract
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 TLE3KO 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.
Highlights
Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men worldwide (Torre et al, 2015)
The androgen-dependent prostate cancer cell line LNCaP is sensitive to androgen receptor (AR) inhibitors such as apalutamide (Figure 1—figure supplement 1A) and enzalutamide (Figure 1—figure supplement 1B), making it a model system well-suited for the unbiased discovery of novel regulators of AR inhibitor sensitivity in prostate cancer cells
The efficacy of the AR antagonists enzalutamide and apalutamide illustrates the importance of persistent signaling through the AR pathway in castration-resistant prostate cancer (CRPC) (Clegg et al, 2012; Beer et al, 2014)
Summary
Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men worldwide (Torre et al, 2015). Deregulated androgen receptor (AR) signaling is a major driver of prostate cancer (Taylor et al, 2010). Androgen deprivation therapy (ADT) is used to treat locally advanced and metastatic prostate cancer, achieving remission in most patients. Despite castrate-levels of androgens in the serum, the disease inevitably progresses to a castration-resistant state (Perlmutter and Lepor, 2007). AR signaling remains a pivotal driver in castration-resistant prostate cancer (CRPC), which is illustrated by the efficacy of AR-
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