The 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 a majority of 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. The high prevalence of these rearrangements, and their biological significance represents a novel therapeutic target for the treatment of prostate cancer.
We recently demonstrated that the small molecule YK-4-279 inhibits ERG and ETV1 biological activity in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present our findings in an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP and fusion-negative PC-3 tumors. Animals were treated with YK-4-279 and its effect on tumor size, lung metastasis and survival were observed. YK-4-279 treatment resulted in decreased tumor size in the LNCaP cohort only. A reduction in tumor metastasis to the lungs was observed in compound treated LNCaP animals with comparable tumor sizes. YK-4-279 also increased survival in LNCaP mice. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 was reduced as well. ETS fusion-negative PC-3 xenografts were unresponsive to the compound. YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. As part of this study, we also established that (S) -YK-4-279 is the active enantiomer in prostate cancer cells. (S) -YK-4-279 binds to ETV1 with comparable kinetics as the racemic mixture and inhibits ETV1 activity. (R) -YK-4-279 does not demonstrate ETV1 binding or inhibition.
Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and should be further evaluated for its clinical applications in prostate cancer.
Citation Format: Said Rahim, Sarah Justvig, Sung-Hyeok Hong, Perrer Tosso, Haydar Celik, Yasemin Sayedigar-Kont, Milton Brown, Colm Morrissey, Jeffrey Toretsky, Aykut Üren. YK-4-279 is a small molecule inhibitor of ETV1 and inhibits metastasis in a mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2949. doi:10.1158/1538-7445.AM2014-2949