Inhibition of GATA2 in prostate cancer by a clinically available small molecule. Issue 1 (24th November 2021)

• Record Type: Journal Article
• Authors: Kaochar, Salma; Rusin, Aleksandra; Foley, Christopher; Rajapakshe, Kimal; Robertson, Matthew; Skapura, Darlene; Mason, Cammy; Berman De Ruiz, Karen; Tyryshkin, Alexey Mikhailovich; Deng, Jenny; Shin, Jin Na; Fiskus, Warren; Dong, Jianrong; Huang, Shixia; Navone, Nora M; Davis, Christel M; Ehli, Erik A; Coarfa, Cristian; Mitsiades, Nicholas
• Is Part Of: Endocrine-related cancer. Volume 29:Issue 1(2022)
• Page Start: 15
• Page End: 31
• Publication Date: 2021-11-24
• Subjects: prostate cancer -- castration-resistance -- GATA2 -- Dilazep -- c-MYC; Endocrine glands -- Cancer -- Periodicals; Endocrinology -- Periodicals; Cancer -- Endocrine aspects -- Periodicals; 616.9944005
• DOI: 10.1530/ERC-21-0085
• Languages: English
• ISSNs: 1351-0088

Abstract

Abstract : Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo . Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.