Researchers Identify Irreversible Inhibitor for KRAS Gene Mutation
Cancer researchers at UT Southwestern Medical Center have discovered a molecule that selectively and irreversibly interferes with the activity of a mutated cancer gene common in 30% of tumors. The molecule, SML-8-73-1 (SML), interferes with the KRAS gene, whose proteins influence when cells divide. KRAS mutations are found in cancers of the lung, pancreas, and colon, and mutation carriers are less responsive to therapy. The study by Hunter et al was published in Proceedings of the National Academy of Sciences.
“RAS proteins including KRAS have not been ‘druggable’ for many decades despite a lot of effort from academia and industry,” said senior author Kenneth Westover, MD, PhD, Assistant Professor of Radiation Oncology and Biochemistry, and a member of UT Southwestern’s Harold C. Simmons Cancer Center.
“We are exploring irreversible inhibitors as a solution, which we believe may pave the way for the development of KRAS-targeted compounds with therapeutic potential and perhaps compounds that target other RAS family proteins involved in cancer,” Dr. Westover said.
First Irreversible KRAS Inhibitor
Building on previous work, Dr. Westover and fellow investigators used a technique called x-ray crystallography to determine what happens when SML is added to KRAS carrying the G12C mutation, a hallmark of tobacco-associated lung cancer and present in 25,000 of the new cases of lung cancer in the United States annually.
Researchers found that SML irreversibly binds to mutated KRAS, making the KRAS G12C inactive. SML competes with molecules that KRAS naturally binds to, called GTP and GDP, and is not removable, even when GTP and GDP are present at very high levels.
The researchers then used a technique called mass spectrometry to determine that SML is not only irreversible, but selective: the molecule binds only to KRAS and not the roughly 100 other members of the RAS protein family that have very similar structures.
“We believe SML may be the first irreversible and selective inhibitor of KRAS,” said Dr. Westover. “As a next step, we are improving the SML compound to facilitate studies involving living cancer cells, and eventually animals and humans.”
Dr. Westover is the corresponding author for the Proceedings of the National Academy of Sciences article.
The study was supported by the Cancer Research and Prevention Institute of Texas and The Welch Foundation.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
