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

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.

Mechanisms of enzalutamide resistance in castration‐resistant prostate cancer and therapeutic strategies to overcome it

“…SPT (Lam et al, 2020) AVPR1A (Zhao et al, 2019) NK cells/microRNA-34, microRNA-449/AR-V7, EZH2 (Lin et al, 2017) HSP70/STUB1/AR-V7 (Liu et al, 2018) AKR1C3/AR-V7 (Liu, Yang, et al, 2019) AR-V7 ABT263 (BCL2 protein inhibitor)/IPI-9119 (fatty acid synthase inhibitor)/luteolin/CDDO-Me/degarelix (Cucchiara et al, 2019;Khurana et al, 2020;Naiki-Ito et al, 2019;Zadra et al, 2019) c-Myc/AR-Vs, AR-FL Quiflapon (5-Lox inhibitor) (Bai et al, 2019;Monga et al, 2020) GATA2/AR-FL, AR-Vs (Joseph et al, 2013;Korpal et al, 2013;Wang et al, 2016) F877L, H875Y, T878A/D891H, T878A/S889G ODM-201 (Borgmann et al, 2018;Lallous et al, 2016;Prekovic et al, 2016) GR overexpression AMFR-11β-HSD2 (Li, Alyamani, et al, 2017) TLE3 (Palit et al, 2019) PI3K/AKT/GR…”

“…The loss of 11β‐hydroxysteroid dehydrogenase‐2 could also be mediated by ubiquitin E3‐ligase autocrine mobility factor receptor, leading to enzalutamide resistance. In a genome‐wide CRISPR‐Cas9 screening study, it was found that the loss of transducin‐like enhancer of split 3 in conjunction with androgen receptor inhibition resulted in glucocorticoid receptor up‐regulation, which led to enzalutamide resistance in LNCaP cells (Palit et al, 2019). Hence, transducin‐like enhancer of split 3 is involved in the regulation of glucocorticoid receptor expression and drug resistance, providing a novel target for enzalutamide‐resistant castration‐resistant prostate cancer treatment.…”

Mechanisms of Enzalutamide Resistance in Castration-Resistant Prostate Cancer and Therapeutic Strategies to Overcome It

“…Moreover, ubiquitin E3-ligase autocrine mobility factor receptor (AMFR) mediated the loss of 11β-HSD2, leading to Enz resistance. In a genome-wide CRISPR-Cas9 screening study (Palit, Vis et al, 2019), researchers found that the loss of transducin-like enhancer of split 3 (TLE3) in conjunction with AR inhibition by the GR enhancer resulted in GR upregulation, which led to Enz resistance in LNCaP cells. Hence, TLE3 was involved in the regulation of GR expression and drug resistance, providing a novel target for Enz-resistant CRPC treatment.…”

A kinome-centered CRISPR-Cas9 screen identifies activated BRAF to modulate enzalutamide resistance with potential therapeutic implications in BRAF-mutated prostate cancer

“…Acquired resistance to enzalutamide has been the focus of intense research, and several mechanisms have been described. These resistance mechanisms include activation of other signaling pathways such as the PI3K pathway 8 , NF-κB signaling 9 and glucocorticoid receptor (GR) overexpression 10 , 11 .…”

“…Functional genetic screens using CRISPR-Cas9 are a powerful tool for the unbiased identification of genes that have a central role in a wide range of biological processes in various genetic and pharmacological backgrounds, including cancer 11 , 13 , 14 . For example, through a genome-wide CRISPR-Cas9 screen, TLE3 was identified as a novel modulator of enzalutamide sensitivity which, together with AR, regulates GR expression and drug response in prostate cancer 11 . Using a similar approach, we set out to identify kinases whose inhibition could potentiate enzalutamide efficacy in prostate cancer cells, with the aim to discover biomarkers for resistance and potential drug combinations that are able to overcome enzalutamide resistance.…”