GATA2 up-regulation restores androgen receptor chromatin association and advances darolutamide resistance in prostate cancer

Darolutamide is an anti-androgen drug clinically used for prostate cancer therapy. Despite its efficacy, potential drug resistance poses significant challenges in the clinical setting. To better understand the molecular changes resulting from prolonged exposure to darolutamide, we developed a darolutamide-resistant model using LNCaP prostate cancer cells. Through ChIP-seq analysis, we found that a temporary treatment of cells with darolutamide effectively disrupts AR binding to chromatin. However, in darolutamide-resistant cells, the chromatin binding of AR is largely restored. By an integrative analysis of ChIP-seq and RNA-seq, we further identified GATA2, a pioneer factor for AR, substantially upregulated in darolutamide-resistant cells. GATA2 plays an essential role in promoting the proliferation of darolutamide-resistant cells and directly contributes to drug resistance. The ablation of GATA2 by siRNA abolished AR's recruitment to chromatin, leading to a significant reduction in gene expression regulated by AR in these resistant cells. Conversely, the overexpression of GATA2 in prostate cancer cells promoted cell proliferation and resistance to darolutamide. This study demonstrates the significance of GATA2 in the development of darolutamide resistance and suggests GATA2 as a promising therapeutic target to overcome this resistance. Our research highlights the crucial role of the AR and GATA2 interplay in prostate cancer progression and identifies GATA2 as a potential therapeutic target. Previously GATA2 has been shown to be linked to poor prognosis in prostate cancer, but no clinically applicable GATA2 inhibitor is yet available. K7174, a known proteasome inhibitor that inhibits GATA2, enhanced the killing activity of AML chemotherapeutics in vitro. When we combined K7174 with darolutamide in our study, the prostate cancer cells displayed increased sensitivity to darolutamide. This suggests that such a combination could enhance therapeutic outcomes and has the potential to delay or even prevent the onset of resistance. However, the clinical use of proteasome-targeting agents often comes with substantial side effects. Prostate cancer patients will benefit from future studies on the development of more specific and potent GATA2 inhibitors with less toxicity.