UTSW findings advance RAS inhibitors to fight more cancers: newsroom

DALLAS – November 4, 2021 – New findings from researchers at UT Southwestern help better understand how one of the most mutated cancer genetic drivers carries the signals that cause disease.

Kenneth Westover, MD, Ph.D., associate professor of radiation oncology and biochemistry

The study, published in Nature Structural and molecular biology, focuses on a family of proteins called RAS, which is mutated in 20-25% of all cancers, especially fatal cancers such as pancreatic, colorectal and lung cancers.

“A framework for developing RAS inhibition strategies is absolutely necessary because recently approved RAS inhibitors such as sotorasib only work against a specific mutation, and many other RAS mutations also cause cancer,” said Kenneth Westover, MD, Ph.D., associate professor of radiation oncology and biochemistry, member of the Harold C. Simmons Comprehensive Cancer Center Chemistry and Cancer Research Program at UT Southwestern, and study author. “This work paves the way for the development of new targeted inhibitors of RAS to fight the main drivers of fatal cancers, such as pancreatic and colon cancer. “

Starting in 2012, Dr. Westover’s lab worked with the Dana-Farber Cancer Institute to develop drugs that bind to a specific RAS mutant where a glycine amino acid at position 12 in the RAS protein is transformed into a cysteine, the so-called KRAS G12C.

“Cysteine ​​is a distinctive amino acid that allows us to irreversibly bind drugs using special chemistries. Other major RAS mutations associated with cancer don’t give us the same footing, ”said Dr Westover.

His lab’s work helped propel the field that saw the approval of a KRAS G12C inhibitor, sotorasib, in May. The approval of an analogue drug, adagrasib, is widely awaited.

In the latest study, Westover’s lab set out to understand how carcinogenic RAS mutants transmit inappropriate signals from the cell surface to the cell nucleus. The formation of large clumps of proteins as part of the mechanism was known, but the structure of the clusters was unknown. Dr Westover and his colleagues used computer simulations to arrive at an atomistic structural model of a RAS assembly and validated the model using biological systems.

“This structural model is now available to the entire RAS research community. We hope this will allow researchers to test new ideas on how RAS works in normal physiology and new strategies to target cancer-causing RAS mutations, ”said Carlos L. Arteaga, MD, director of the Simmons Cancer Center.

Since RAS signaling relies on the formation of RAS complexes, Dr. Westover believes that it may be possible to create new generations of RAS-targeting drugs that work by separating these RAS complexes.

Funding for the study comes from the National Cancer Institute, the Department of Defense, and the Cancer Prevention and Research Institute in Texas.

The Simmons Cancer Center, the only comprehensive cancer center designated by the National Cancer Institute in North Texas, includes five research programs and 12 clinical care programs focused on promoting breakthrough translational research that can improve the treatment of patients, address cancer health disparities and prevent cancer globally. . In addition, the Centre’s education and training programs support and develop the next generation of cancer researchers and clinicians. The full designation and associated funding is designed to support Simmons Cancer Center research and to provide patients with access to innovative clinical trials with promising new drugs. Members of the Simmons Cancer Center currently have over $ 90 million in extramural cancer research funding.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has been awarded six Nobel Prizes and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine and 14 researchers of the Howard Hughes Medical Institute. The full-time faculty of more than 2,800 is responsible for revolutionary medical advancements and is committed to rapidly translating science-driven research into new clinical treatments. Doctors at UT Southwestern provide care in approximately 80 specialties to more than 117,000 inpatients, more than 360,000 emergency room cases and supervise nearly 3 million outpatient visits per year.