Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth.

Ahmed A Mohamed,Gyorgy Petrovics,Shyh-Han Tan,Taduru Sreenath,Inger L Rosner,Albert Dobi,Jeffrey Strovel,Lakshmi Ravindranath,Charles P Xavier,Nicole A Laronde,David G Mcleod,Clifton L Dalgard,Shiv Srivastava,Meera Srivastava,Sanjay V Malhotra,Gauthaman Sukumar,Vineet Kumar,Nishat Seraj

doi:10.1158/0008-5472.can-17-2949

Abstract

Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of the most validated and prevalent genomic alterations present in early stages of prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in TMPRSS2-ERG harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-[2-Thiazolylazo]-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature. In vivo, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity-based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.Significance: A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy. Cancer Res; 78(13); 3659-71. ©2018 AACR.

Highlights

Cancer of the prostate (CaP) is estimated to be the most frequently diagnosed non-skin malignancy and second leading cause of cancer-related deaths in 2018 among men in the United States [1]
One compound was observed to significantly increase the ETS-related gene (ERG) protein expression, and upon decoding it was found to be a synthetic androgen. This observation is consistent with the androgen-responsive function of the TMPRSS2 gene promoter [38], fused to ERG in the context of TMPRSS2–ERG gene rearrangement in CaP [11]
Because ERG expression in the TMPRSS2–ERG context is androgen receptor (AR) dependent, we evaluated the effect of ERGi-USU on AR and its downstream target prostate-specific antigen (PSA) in hormone-responsive prostate cancer cell lines

Summary

Introduction

Cancer of the prostate (CaP) is estimated to be the most frequently diagnosed non-skin malignancy and second leading cause of cancer-related deaths in 2018 among men in the United States [1]. Early detected organ confined CaP is managed by active surveillance, surgery, or radiotherapy [2]. A significant subset of patients with CaP (20%–40%) experience. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). A.A. Mohamed and C.P. Xavier contributed to this article

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Conclusion