Health

RAS Inhibitors Used to Fight More Cancer-ScienceDaily

New discoveries by UT Southwestern researchers will help us better understand how one of the most commonly mutated genetic drivers of cancer passes the signal that causes the disease.

Research published in Natural structure and molecular biologyFocuses on a family of proteins called RAS. It is mutated in 20-25% of all cancers, especially in deadly cancers such as pancreatic cancer, colorectal cancer, and lung cancer.

“Recently approved RAS inhibitors, such as sotrasiab, act on only one particular mutation, and many other RAS mutations also cause cancer, so the framework for developing RAS inhibitor strategies is very high. It is necessary, “said Kenneth Westover, an associate professor of medicine. Radiation Oncology and Biochemistry, Member of the Chemistry and Cancer Research Program at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center and author of the study. “This study sets the stage for the development of new targeted RAS inhibitors to address key drivers of lethal cancers such as pancreatic and colon cancers.”

Since 2012, Dr. Westover’s lab has worked with the Dana-Farber Cancer Institute to develop a drug that binds to a specific RAS variant, the so-called KRASG12C, in which the glycine amino acid at position 12 of the RAS protein is converted to cysteine. .. ..

“Cysteine is a unique amino acid that can irreversibly attach drugs using special chemicals. Other major cancer-related RAS mutations do not give us the same foothold,” Westover said. The doctor said.

The work of his laboratory helped promote the area where one KRASG12C inhibitor, sotrasib, was approved in May. Approval of a similar drug, adaglassib, is widely expected.

In the latest study, the Westover Institute sought to understand how cancer-causing RAS mutants pass inappropriate signals from the cell surface to the cell nucleus. The formation of large protein clusters as part of the mechanism was known, but the structure of the clusters was unknown. Dr. Westover and his collaborators used computer simulations to reach an atomic structure model of the RAS assembly and used a biological system to validate the model.

“This structural model is now available to the wider RAS research community. Researchers have new ideas on how RAS works in normal physiology and new strategies to target cancer-causing RAS mutations. I hope we can test it, “says Dr. Carlos L. Arteaga. , Director of Simmons Cancer Center.

Since RAS signaling depends on the formation of RAS complexes, Dr. Westover believes that degrading such RAS complexes may create a new generation of RAS-targeted drugs that work. increase.

This study was funded by the National Cancer Institute, the Department of Defense, and the Texas Cancer Prevention Institute.

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material Provided by UT Southwestern Medical Center.. Note: The content can be edited in style and length.

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2/ https://www.sciencedaily.com/releases/2021/11/211104162559.htm

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