Small molecule inhibitor acted on mutated ETS transcription factors to reduce cell invasiveness and motility.
Scientists claim a small molecule drug initially developed to block an oncoprotein in Ewing’s sarcoma also has potential against prostate cancer. In vitro studies by the team at Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, have found that their compound inhibits two ETS family transcription factors in human prostate cancer cells.
This inhibition reduced prostate cancer cell motility and invasion capabilities. Lombardi associate professor Aykut Üren, M.D., and colleagues report their findings in PloS One in a paper titled “YK4279 inhibits ERG and ETV1 mediated prostate cancer cell invasion.”
Genomic rearrangements involving the ETS family of transcription factors occur in 40–70% of prostate cancer cases, with ERG and ETV1 representing the most commonly altered ETS members, the Lombardi team explains. In Ewing’s sarcoma, translocation in the gene for a related ETS family protein, FLI1, leads to the generation of an oncogenic fusion protein known as EWS-FLI1, which is the target for potential Ewing’s sarcoma drugs.
One such candidate developed by Dr. Üren’s team, designated YK-4-279, has been found to inhibit EWS-FLI1 activity, induce apoptosis in Ewing’s sarcoma cell lines, and slow down tumor growth in mouse xenograft models. Because of the close homology between FLI1, ERG, and ETV1, the researchers tested the ability of YK-4-279 to inhibit ETS gene activity in prostate cancer cell lines. They used two cell lines that demonstrated either androgen-dependent ERG or ETV1 rearrangements and expression but not FLI1 expression.
Exposing the cancer cells to YK-4-279 significantly reduced the mRNA and protein levels of several of ERG and ETV1’s target genes in the respective cell lines. The level of downregulation was comparable to that obtained using siRNA-mediated gene knockdown, they report.
Significantly, inhibition of ERG and ETV1 protein activity in terms of expression of their targets was obtained without any significant decrease in actual ERG or ETV1 protein levels. “These results suggest that YK-4-279 is able to inhibit ERG and ETV1 transcriptional activity in prostate cancer cells, leading to decreased expression of genes that are involved in breakdown of extracellular matrix and metastasis,” the authors write.
Cell invasion assays separately showed that administering non-cytotoxic levels of YK-4-279 to the cancer cells significantly reduced their ability to infiltrate an endothelial monolayer. They confirmed this effect was due to YK-4-279 by demonstrating that the compound had no affect on the invasive ability of fusion-negative, non androgen-responsive PC-3 prostate cancer cells. Transiently expressing ERG in PC-3 cells was enough to give these cells a more invasive phenotype, while treating ERG-expressing PC-3 cells with YK-4-279 significantly dampened this invasive ability.
The researchers separately showed that YK-4-279 administration significantly reduced the motility of prostate cancer cell line that expressed high basal levels of ETV1 but had no effect on the motility of the negative control PC-3 cells. Because YK-4-279 was found to act differently on the DNA binding of EWS-FLI1, ETV1, and ERG, the researchers propose the drug inhibits ETV1 and ERG function in prostate cancer cells by preventing protein-protein interactions that differ from those of EWS-FLI1 in Ewing’s sarcoma.
“Currently, androgen dependent signaling pathways in prostate cancer are targeted via castration and androgen receptor antagonists,” the authors note. “The effects of these treatments can be in part attributed to the downregulation of rearranged ETS factors. Thus, the successful development of small molecule inhibitors of ERG and ETV1, such as YK-4-279, will represent a novel line of therapeutics aimed at preventing or treating metastatic disease, while saving patients the long-term effects of therapies targeting the androgen pathway.”