DALLAS July 28, 2014 UT Southwestern Medical Center cancer researchers have found a molecule that selectively and irreversibly interferes with the activity of a mutated cancer gene common in 30 percent of tumors.
The molecule, SML-8-73-1 (SML), interferes with the KRAS gene, or Kirsten rat sarcoma viral oncogene homolog. The gene produces proteins called K-Ras that influence when cells divide. Mutations in K-Ras can result in normal cells dividing uncontrollably and turning cancerous. These mutations are particularly found in cancers of the lung, pancreas, and colon. In addition, people who have the mutated gene are less responsive to therapy.
Researchers have unsuccessfully tried to develop a drug to inhibit K-Ras for some 30 years.
"RAS proteins including KRAS have not been 'druggable' for many decades despite a lot of effort from academia and industry," said senior author Dr. Kenneth Westover, 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.
Dr. Westover works as both a clinician as a member of the Lung Radiation Oncology Team at the Simmons Cancer Center, and as a researcher. The Westover laboratory investigates the molecular basis of cancer with an eye toward developing compounds that perturb cancer biology, and therefore have potential to become therapies. Dr. Westover's lab has been particularly targeting KRAS because this gene is the most commonly mutated oncogene in cancer.
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
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UT Southwestern Medical Center