Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR-related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient-derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive-tumor gene programs including those of epithelial-mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed-forward loops in hyperactive AR and RORγ signaling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR-V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.

Deregulation of Cholesterol Homeostasis by a Nuclear Hormone Receptor Crosstalk in Advanced Prostate Cancer

“…Our previous studies showed that RORγ is overexpressed and plays a crucial role in mCRPC tumors [25,27]. As demonstrated in our previous studies [25,27,28], small molecule antagonists (also known as inverse agonists) of RORγ such as XY018 or SR2211 potently inhibited the growth and survival of mCRPC cells (Figure 1a,b).…”

“…Our previous studies showed that RORγ is overexpressed and plays a crucial role in mCRPC tumors [25,27]. As demonstrated in our previous studies [25,27,28], small molecule antagonists (also known as inverse agonists) of RORγ such as XY018 or SR2211 potently inhibited the growth and survival of mCRPC cells (Figure 1a,b). Given that elevated cholesterol levels promote PCa cell growth and survival, we thus investigated whether the effect of RORγ inhibition is linked to its potential function in control of the increased cholesterol level in mCRPC.…”

Identification of Pathologic and Prognostic Genes in Prostate Cancer Based on Database Mining

“…However, the mechanism has not been revealed. Moreover, PBK was a downstream target of RORγ that exerted the cellular effects, indicating that PBK , RORγ , and AR were all associated with the growth and survival of aggressive prostate cancer ( Zhang et al, 2021 ). However, possible mechanisms in non-aggressive prostate cancer have not been researched.…”

Natural compounds ursolic acid and digoxin exhibit inhibitory activities to cancer cells in RORγ-dependent and -independent manner

“…Recently, in search for alternative therapeutic targets for advanced cancer, RORγ in tumor cells was identified to play a critical role in tumor progression in certain types of cancer ( Zou et al, 2022a ), including castration-resistant prostate cancer (CRPC) ( Wang et al, 2016 ; Wang et al, 2020 ; Zheng et al, 2020 ; Zhang et al, 2021 ), triple-negative breast cancer (TNBC) ( Cai et al, 2019 ; Zou et al, 2022b ), small cell lung carcinoma (SCLC) ( Chen et al, 2022 ) and pancreatic ductal adenocarcinoma (PDAC) ( Lytle et al, 2019 ). In CRPC tumors and cells, RORγ directly activates androgen receptor (AR) expression and AR signaling ( Wang et al, 2016 ; Zheng et al, 2020 ; Zhang et al, 2021 ). In TNBC cells and tumors, RORγ acts as a master activator of tumor cholesterol biosynthesis program ( Cai et al, 2019 ; Zou et al, 2022b ).…”