A Small Molecule Inhibitor of ETV1, YK-4-279, Prevents Prostate Cancer Growth and Metastasis in a Mouse Xenograft Model

Abstract

BackgroundThe erythroblastosis virus E26 transforming sequences (ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.Methods and FindingsWe recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S)-YK-4-279 is the active enantiomer in prostate cancer cells.ConclusionOur results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential therapeutic tool for treatment of human prostate cancer at different stages.

COP1 is downregulated in renal cell carcinoma (RCC) and inhibits the migration of RCC ACHN cells in vitro

“…Furthermore, an increased expression level of MMP7 was demonstrated in high-grade RCC tumors (27). A previous study demonstrated that ETV1 bound to the MMP7 gene promoter and stimulated MMP7 expression (28). The present study demonstrated that overexpressed COP1 reduced the MMP7 expression levels, along with the downregulation of ETV1.…”

ETS transcription factors as emerging drug targets in cancer

“…In addition, YK‐4‐279 has been shown to antagonize ERG and ETV1 activities in prostate cancer; it inhibited ERG‐ and ETV1‐driven transcriptional activity, and reduced invasion of VCaP and LNCaP cells, respectively . However, the exact mode of binding between YK‐4‐279 and ERG has yet to be determined, and there are issues related to its toxicity and pharmacokinetics, as previously reported . The development of its derivative TK216 is currently in phase 1 trial (ClinicalTrials.gov Identifier: NCT02657005) that can impact the future development of ETS‐targeted therapies.…”

“…77 However, the exact mode of binding between YK-4-279 and ERG has yet to be determined, and there are issues related to its toxicity and pharmacokinetics, as previously reported. 78 The development of its derivative TK216 is currently in phase 1 trial (ClinicalTrials.gov Identifier: NCT02657005) that can impact the future development of ETS-targeted therapies.…”

Synergistic Activity with NOTCH Inhibition and Androgen Ablation in ERG-Positive Prostate Cancer Cells

“…Accumulating evidence has established that ERG is a key regulator that controls the activity of various signaling pathways recognized as key oncogenic drivers in various malignancies including CaP (12–14). Given the high incidence and mounting evidence supporting its oncogenic role, ERG and components of ERG network have emerged as promising drug targets for CaP therapies (15–18). However, the prevailing notion is that oncogenic nuclear transcription factors such as ERG are challenging therapeutic targets.…”