New Anticancer Strategy Reduces Toxicity of Targeting RNR

The enzyme ribonucleotide reductase (RNR) is a bottleneck for cancer cell growth. In a study published last Friday in Nature Communications, Emory University scientists present a method of targeting ribonucleotide reductase that may avoid the toxicity of previous approaches. The findings may inform more focused drug discovery efforts.

Cancer researchers have long had an interest in ribonucleotide reductase, since it converts RNA components (ribonucleotides) into DNA building blocks (deoxyribonucleotides)—which cancer cells need in abundance for fast growth. Several more traditional chemotherapy drugs, such as hydroxyurea, fludarabine, cladribine, and gemcitabine, inhibit ribonucleotide reductase by different mechanisms.

In the present study, the researchers found that RRM2, one of ribonucleotide reductase’s two parts, is regulated by an acetyl group tag. When acetylation occurs at a particular site, RRM2 is inactivated because certain molecules of RRM2 are prevented from pairing up. The researchers also identified an enzyme called Kat7 that adds the tag.

“Based on our findings, we will develop novel anticancer agents that inhibit ribonucleotide reductase activity by directly regulating RRM2 acetylation in cancer cells,” says first author Xingming Deng.

In addition, the team observed that Sirt2, an enzyme that removes acetylation from RRM2 (thus activating it), is more abundant in samples from lung cancer patients. The authors suggest that Sirt2 could be a prognostic biomarker for lung cancer.

Sirt2 has been a hot target for anticancer researchers already, but as Sirt2 is part of the sirtuin family, it has been difficult to develop inhibitors against it that don’t inhibit other sirtuins. But the new results provide fresh insights into how Sirt2 inhibitors preferentially affect cancer cells.