Corporate Banner
Satellite Banner
Proteomics
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

UTSW Cancer Researchers Identify Irreversible Inhibitor for KRAS Gene Mutation

Published: Tuesday, July 29, 2014
Last Updated: Monday, July 28, 2014
Bookmark and Share
Irreversible inhibitor for KRAS gene mutation involved in lung, colon, and pancreatic cancers.

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 G12C mutation, a hallmark of tobacco-associated lung cancer and present in 25,000 of the new cases of lung cancer in the U.S. 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. This attribute is what makes SML an irreversible inhibitor - neither GDP nor GTP are able to knock it off and take its place.

The researchers then used a technique called mass spectrometry to determine that SML is not only irreversible, but selective - binding 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, who was recruited to UT Southwestern with funds from the state-funded Cancer Research and Prevention Institute of Texas. “As a next step, we are improving the SML compound to facilitate studies involving living cancer cells, and eventually animals and humans.”


Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,400+ scientific posters on ePosters
  • More than 3,700+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Cell that Replenishes Heart Muscle Found by UT Southwestern Researchers
Researchers devise a new cell-tracing technique to detect cells that do replenish themselves.
Tuesday, June 23, 2015
Researchers Find Molecular Mechanisms within Fetal Lungs that Initiate Labor
Biochemists found that steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2) proteins control genes.
Tuesday, June 23, 2015
MAGE Genes Provide Insight into Optimizing Chemotherapy
UT Southwestern Medical Center scientists have identified a new biomarker that could help identify patients who are more likely to respond to certain chemotherapies.
Tuesday, February 17, 2015
Researchers Find New Mechanism That Controls Immune Responses
The findings appear online in the journal Science.
Friday, February 13, 2015
Protein Variant may Boost Cardiovascular Risk by Hindering Blood Vessel Repair
Researchers have found that apoE3 helps repair the lining of blood vessels.
Friday, September 19, 2014
UT Southwestern Researcher Selected for ASBMB Merck Award
Award recognizes Dr. Zhijian Chen’s outstanding contributions to research in biochemistry and molecular biology.
Friday, July 18, 2014
Cellular Force That Drives Allergy and Asthma Can be Blocked by Interferon
Type I interferons block the development of allergy- and asthma-driving Th2 cells.
Friday, June 20, 2014
Proteins Causing Daytime Sleepiness Also Tied to Bone Formation
Orexin proteins provide target for osteoporosis, UT Southwestern researchers find.
Saturday, June 14, 2014
New Mechanism Explains How Cancer Cells Spread
A protein critical to the spread of deadly cancer cells has been identified and how it works determined.
Wednesday, May 28, 2014
Stem Cell Study Opens Door to Undiscovered World of Biology
Discovery published in Nature measures protein production.
Tuesday, March 11, 2014
Dr. Beth Levine Receives 2014 Stanley J. Korsmeyer Award
Award recognizes Dr. Levine’s fundamental contributions to the understanding of autophagy.
Friday, February 07, 2014
Two UT Southwestern Scientists Earn Spots on Top 20 List
Dr. Eric Olson and Dr. Philip Thomas earn spots in translational research.
Saturday, February 01, 2014
Study Identifies Potential Therapeutic Target for Incurable, Rare Type of Soft-Tissue Cancer
UT Southwestern scientists study published online in Cell Reports.
Friday, December 27, 2013
Overexpressed Protein A Culprit in Certain Thyroid Cancers
Study by UT Southwestern researchers suggests a link between nervous system and cancer.
Tuesday, October 15, 2013
Cellular Switch Controls Growth of Brain Tumor Cells
Researchers investigate that the protein RIP1 acts as a mediator of brain tumor cell survival.
Tuesday, September 24, 2013
Scientific News
New Tech Enables Epigenomic Analysis with a Mere 100 Cells
A new technology that will dramatically enhance investigations of epigenomes, the machinery that turns on and off genes and a very prominent field of study in diseases such as stem cell differentiation, inflammation and cancer has been developed by researchers at Virginia Tech.
TOPLESS Plants Provide Clues to Human Molecular Interactions
Scientists at Van Andel Research Institute have revealed an important molecular mechanism in plants that has significant similarities to certain signaling mechanisms in humans, which are closely linked to early embryonic development and to diseases such as cancer.
Toxin from Salmonid Fish has Potential to Treat Cancer
Researchers from the University of Freiburg decode molecular mechanism of fish pathogen.
Study Finds Non-Genetic Cancer Mechanism
Cancer can be caused solely by protein imbalances within cells, a study of ovarian cancer has found.
Long-sought Discovery Fills in Missing Details of Cell 'Switchboard'
A biomedical breakthrough reveals never-before-seen details of the human body’s cellular switchboard that regulates sensory and hormonal responses.
Rice Disease-Resistance Discovery Closes the Loop for Scientific Integrity
Researchers reveal how disease resistant rice detects and responds to bacterial infections.
The Mystery of the Instant Noodle Chromosomes
Researchers from the Lomonosov Moscow State University evaluated the benefits of placing the DNA on the principle of spaghetti.
New Mussel-Inspired Surgical Protein Glue
Korean scientists have developed a light-activated, mussel protein-based bioadhesive that works on the same principles as mussels attaching to underwater surfaces and insects maintaining structural balance and flexibility.
Vital Protein in Healthy Fertilization Process Identified
Researchers at the National Institutes of Health have discovered a protein that plays a vital role in healthy egg-sperm union in mice.
Teeth Reveal Lifetime Exposures to Metals, Toxins
Researchers have identified dental biomarkers to reveal links between early iron exposure and late life brain diseases.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,400+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,700+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FREE!