UNC Lineberger’s Channing Der, PhD, and colleagues have made new findings that could help researchers identify treatments for cancers with mutations in the RAS gene family, which are among the most highly mutated genes in cancer.
Earlier research by Der helped to discover mutations in the RAS gene that are linked to human cancer. While this was the first human oncogene to be identified, researchers now know of many more genes that are mutated in the disease.
Despite more than three decades of research, treatments to target these cancer-driving RAS genes — KRAS, NRAS and HRAS — have remained elusive. In a , Der and colleagues were able to screen chemical reagents to help researchers in the search for RAS-targeted therapies. published in the journal Science Signaling
“A successful anti-RAS drug has yet to reach the cancer patient,” said Der, the Sarah Graham Kenan Distinguished Professor in the UNC School of Medicine Department of Pharmacology. “One factor that has compromised these efforts has been the lack of well-evaluated reagents to study the three RAS genes. In our study, we completed a careful and thorough validation of antibodies to study RAS. Our study will provide a critical guideline to improve future RAS studies.”
They rigorously tested reagents to identify those that accurately recognized each of the four RAS proteins made by the three different RAS genes.
“A number of companies sell antibodies for these RAS proteins. The problem is – they’re not properly validated,” said the study’s first author Andrew Waters, PhD, a postdoctoral researcher in Der’s lab. “What they haven’t been able to do in the past is determine if these antibodies are truly specific to KRAS, HRAS, or NRAS. So we evaluated a bunch of them.”
Waters said they were able to determine which of the commercial antibodies could properly identify the HRAS, NRAS, and KRAS proteins using unique scientific tools. Specifically, they have cells that lack the RAS gene. If the antibody falsely identifies a protein in those models, they know that it is not properly screening for RAS.
“We have tools that normal commercial companies don’t have, and that allowed us to examine the antibodies on a level that they haven’t been examined to before, and truly determine which are specific for KRAS, and which are specific to HRAS or NRAS,” Waters said.
They hope their findings will help address an issue in the field – that many scientific studies cannot be reproduced. By selecting the antibodies that work accurately against RAS, they can improve the quality of research. They plan to use their findings in their own research on pancreatic cancer. Der said his lab will study KRAS in pancreatic and lung cancer, NRAS in melanoma, and HRAS in head and neck cancers.
“Our studies, done in collaboration with the National Cancer Institute RAS Initiative, will help the RAS field in efforts to develop drugs to treat RAS-mutant cancers,” Der said. “The need is great, in particular for pancreatic cancer, where the development of RAS therapies has been identified as one of the four major initiatives for the field.”
In addition to Der and Waters, other authors include Irem Ozkan-Dagliyan, Angelina V. Vaseva, Nicole Fer, Leslie A. Strathern, G. Aaron Hobbs, Basile Tessier-Cloutier, William K. Gillette, Rachel Bagni, Gordon R. Whiteley, James L. Hartley, Frank McCormick, Adrienne D. Cox, Peter J. Houghton, David G. Huntsman, and Mark R. Philips.
The study was supported by the National Institutes of Health/National Cancer Institute, American Cancer Society, the Pancreatic Cancer Action Network and American Association for Cancer Research. Individual researchers were supported by the Department of Defense, Lustgarten Pancreatic Cancer Foundation, and the NIH/NCI. This work does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.