Reactivating epigenetically silenced genes to treat cancer

Researchers have discovered that inhibiting CDK9, a DNA transcription regulator, reactivates genes that have been epigenetically silenced by cancer. Reactivation leads to restored tumor suppressor gene expression and enhanced anti-cancer immunity. It is the first time this particular kinase has been linked to gene silencing in mammals. The paper appears in the journal Cell.

It has been established that epigenetic mediators of gene silencing present new targets for cancer drugs. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation.

The first author on the report, performed a live cell drug screen with genetic confirmation to identify CDK9 as a target and to develop and test an effective inhibitor - MC180295. This highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) has a broad anti-cancer activityin vitro and is effective in in vivo cancer models.

The new drug is highly selective, potentially avoiding the side effects associated with inhibiting the cell cycle. In the study it showed broad effectiveness against cancer both in vitro and in vivo.

"In addition to reactivating tumor suppressor genes, CDK9 inhibition induces sensitivity to the immune checkpoint inhibitor α-PD-1 in vivo," said the author. "It is an excellent target for epigenetic cancer therapy."