Making de-grade

Among cancer drivers MYC is known as a supervillain—the protein propels multiple tumor types and persistently eludes treatment by current drug and therapeutic approaches. New work from the Koehler lab, published in Cell Chemical Biology, demonstrates a promising new avenue for controlling MYC via CDK9, a protein that plays an important role in regulating MYC expression. Previous attempts to target CDK9 have shown that its prolonged inhibition can lead to a compensatory increase in MYC levels, posing a frustrating challenge. The Koehler group has instead developed a selective CDK9 PROTAC, or proteolysis targeting chimera, a molecule that can be used to induce the degradation of a specific protein.

While protein inhibition and degradation may sound similar, they constitute different approaches to modulating protein activity. Inhibition prevents a protein from functioning through physical binding that interferes with its normal activity. Degradation involves breaking down the protein into smaller fragments, effectively removing it from a cell.

The rapid kinetics of the Koehler group’s PROTAC degrader have allowed the researchers to differentiate the effects of CDK9 degradation versus CDK9 inhibition in regulating MYC. The research team, lead by postdoc Mohammed (Mo) Toure with colleagues from the White lab, Calo lab and Robert A. Swanson (1969) Biotechnology Center, showed that CDK9 degradation leads to a rapid downregulation of MYC and prevents the paradoxical increase observed with inhibition. The difference between the two approaches was also evident in their differential effect on nucleolar homeostasis, a cellular process critical for protein synthesis and regulated by MYC.

More broadly, CDK9 expression has been linked to prognosis and therapy resistance in a wide range of tumors, amplifying the impact of this work for development of CDK9-targeted therapies.

This work was supported in part by the MIT Center for Precision Medicine and a graduate fellowship from the Ludwig Center at MIT.