Regulation of Cancer-Causing Protein Could Lead to New Therapeutic Targets

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Atsuo Sasaki, PhD, in his lab at the Vontz Center for Molecular Studies. Photo by Cindy Starr.

Contact: Katie Pence
513-558-4561
Katie.Pence@uc.edu

CINCINNATI—Researchers with the Cincinnati Cancer Center (CCC) and the University of Cincinnati Cancer Institute have discovered a new regulation for the cancer-causing protein KRas that may help with the development of targeted therapies for patients with a KRas mutation.

Atsuo Sasaki, PhD, a member of the CCC, the UC Cancer Institute and the UC Brain Tumor Center as well as an assistant professor in the division of hematology oncology within the department of internal medicine, is the principal investigator on the study, which is published in the Dec. 13, 2013, online edition of the Journal of Biological Chemistry.

“The mutation of a KRas gene is an essential step in the development of many cancers,” Sasaki says. “In fact, the KRas mutation is present in more than 90 percent of patients with pancreatic cancer, and other research has shown that lung and colon cancers have prevalent mutations of this gene as well.”

Although the KRas mutation is not common in primary brain tumors, Ras is known to play a role in glioblastoma, an aggressive form of brain cancer. Nearly 90 percent of glioblastoma cancers see an increase in Ras activation caused by the overexpression and/or mutations of upstream activators, such as the EGF receptor.  Furthermore, studies using an animal model of glioblastoma demonstrate that aberrant KRas activation induces glioblastoma.

Sasaki says that therapies that target KRas could limit not only primary brain tumors, but also brain metastasis.

“KRas mutation is a driver for lung cancer, and the vast majority of lung cancer metastases occur in the brain,” Sasaki says. “Because there has been no effective molecular approach for  the mutated KRas, and because we have found the cellular machinery that recognizes and chops down the mutated KRas, this finding is likely to form a new basis for targeting oncogenic KRas for brain metastatic lung cancers.”

Researchers in academia and industry have been trying to target KRas pharmaceutically for many years without significant success.

“In this study,” Sasaki says, “we took a unique approach. We use a social amoeboid—a powerful model system — to study Ras signaling and look at the KRas regulation.”

To do this, researchers introduced the oncogenic KRas gene into the social amoeboid and compared its regulation to that of a normal KRas gene.

“We discovered that the cell has a system to recognize the oncogenic KRas and break it down,” he says. “This clearance system led to ubiquitination on oncogenic KRas—which means it is being chopped and trashed.

“With this knowledge, we could increase the clearance of mutated KRas from cancer cells; next steps include finding the gene or protein that starts this process. With this additional piece of the puzzle, we’re one step closer to finding a targeted therapy for various cancer types that harbor KRas mutations.”

This research was funded by grants from the UC Department of Internal Medicine and the Brain Tumor Center, which is part of the UC Neuroscience Institute.

The University of Cincinnati, Cincinnati Children’s Hospital Medical Center and UC Health have created the Cincinnati Cancer Center, a joint effort designed to leverage the strengths of all three organizations in order to provide the best possible cancer diagnostics, research, treatment, and care for individuals in the Tristate region and the nation.

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