Targets Old Bottlenecks Points to New Anticancer Drug Strategy for Winship Cancer Institute Team

Jul 21, 2019 | Emory Winship Cancer Center, Ribonucleotide Reductase, Sirt2

Scientist hands in gloves hold pills, new pill research concept

The enzyme ribonucleotide reductase is a bottleneck for cancer cell growth. Winship Cancer Institute of Emory University Researchers has identified ways of targeting ribonucleotide reductase that may avoid the toxicity of previous approaches, informing drug discovery efforts.

Who was the Lead Preclinical Researcher?

Xingming Deng, MD, Ph.D. 

Where was the Study Published

July 19, Nature Communications

The Study: What is Ribonucleotide Reductase?

It controls the supply of DNA building blocks, which cancer cells need in abundance for fast growth. Cancer researchers have long had an interest in ribonucleotide reductase, which converts RNA components (ribonucleotides) into DNA building blocks. Several more traditional chemotherapy drugs, such as hydroxyurea, fludarabine, cladribine, and gemcitabine, inhibit ribonucleotide reductase by a different mechanism.

The research team led by Xingming Deng, Ph.D., found that one of the ribonucleotide reductase’s two parts (RRM2) is regulated by a tag, called acetylation, and identified another enzyme (Kat7) that adds that tag. Acetylation at a particular site inactivates RRM2 by preventing individual molecule of RRM2 from pairing up.

The Findings

Deng, a professor of radiation oncology at Emory University School of Medicine and director of the discovery theme in the Discovery and Developmental Therapeutics research program at Winship. He noted that “Based on our findings, we will develop novel anticancer agents that inhibit ribonucleotide reductase activity by directly regulating RRM2 acetylation in cancer cells.”

Moreover, Deng and team observed that Sirt2, an enzyme that removes acetylation from RRM2 and activates it, is more abundant in samples from lung cancer patients. Sirt2 could be a prognostic biomarker for lung cancer.

Sirt2: A Hot Target

Already a hot topic for anti-cancer researchers, the Winship results offer new insights into how Sirt2 inhibitors preferentially affect cancer cells. It is part of a family (sirtuins) and has been difficult to develop inhibitors to address—many compounds hit more than one. 

Sirt2 has other substrates besides RRM2. Moreover, RRM2 becomes deacetylated after DNA damage, so Sirt 2 inhibitors could sensitize cancer cells to chemotherapy or radiation.

Funding

  • National Cancer Institute
  • Winship Fashion a Cure Research Scholar Award and the Endowed Chair for Cancer Biology

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