More than 100,000 newly diagnosed cases of cancer each year in the United States are subsequently linked to mutations in the KRAS protein. In response to this urgent problem, a new partnership agreement involving the Frederick National Laboratory for Cancer Research (FNLCR) could help identify significant therapeutic opportunities to target these types of cancers.
Earlier this month, the FNLCR and the Weizmann Institute of Science, located in Rehovot, Israel, signed a contractor Cooperative Research and Development Agreement (cCRADA) with the purpose of identifying small molecules that bind to or influence the activity of KRAS4b—a protein that is frequently mutated in pancreatic, colon, and lung cancers. In fact, 95 percent of all pancreatic cancers have a KRAS mutation.
In normal cells, when KRAS is bound to GTP—a chemical compound that is essential for cell signaling— it is activated and transmits a signal to tell the cell to proliferate. This activity is tightly regulated by GTPase activating protein (GAP), which converts KRAS-GTP to inactive KRAS-GDP. In cancer cells, mutations in KRAS prevent the GAP protein from turning KRAS off, which leads to unregulated cell growth.
A team of investigators at the FNLCR has already solved the structure of mutant KRAS4b bound to a GAP. With the new cCRADA, the Weizmann Institute will take the FNLCR structure and use in silico docking—a cutting-edge computational method that is useful in identifying compounds that can bind to the mutant KRAS-GAP complex and help inactivate mutant KRAS. After those results are determined, the FNLCR will test those compounds to evaluate their efficacy.
“This partnership brings together the structural biology and biochemistry expertise of the RAS Initiative with the computational screening methods developed at the Weizmann Institute to hopefully enable us to identify compounds that will shut down mutant KRAS,” said Andrew Stephen, Ph.D., project lead, RAS Biochemistry and Biophysics and the FNLCR principal investigator on the cCRADA.
The partnership has significant potential in that it could help to identify targeted therapeutic approaches.
“Identification of small molecules that bind in the pockets seen in the recently solved structures of oncogenic KRAS-GTP and its complex with GAP proteins is likely to provide a starting point for the development of a potential drug against KRAS-driven cancer,” explained Dhirendra Simanshu, Ph.D., project lead, RAS structural biology, FNLCR.
The National Cancer Institute established the RAS Initiative in 2013 to create an open model of collaboration among government, academic, and industry researchers to combine efforts and create new, innovative approaches to the complex issue of RAS. More than 30 percent of all cancers are driven by mutations in the RAS family of genes. This has been known for more than three decades, but RAS proteins are difficult to target with cancer therapies and have created major challenges for researchers due to their ability to evade signals that control cell growth.
By Max Cole, staff writer; Photo by Dhirendra Simanshu
Image: Surface representation of the structure of oncogenic mutant of KRAS (colored violet) in complex with GTPase-activating proteins (colored light blue).