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

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 2,600+ scientific posters on ePosters
  • More than 3,800+ 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 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

Physiologists Uncover a New Code at the Heart of Biology
New “code” - the speed limit of assembly - dictate the ultimate function of a given protein.
Thursday, September 24, 2015
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
Scientific News
Key to Natural Detoxifier’s Reactivity Discovered
Results have implications for health, drug design and chemical synthesis.
New Protein Found in Immune Cells
Immunobiologists from the University of Freiburg discover Kidins220/ARMS in B cells and demonstrate its functions.
Cell's Waste Disposal System Regulates Body Clock Proteins
New way to identify interacting proteins could identify potential drug targets.
How a Molecular Motor Untangles Protein
Diseases such as Alzheimer’s, Parkinson’s and prion diseases, all involve “tangled” proteins.
Compound Doubles Up On Cancer Detection
Researchers have found that tagging a pair of markers found almost exclusively on a common brain cancer yields a cancer signal that is both more obvious and more specific to cancer.
How Cell Growth Triggers Cell Division
Researchers in Jan Skotheim's lab have discovered a previously unknown mechanism that controls how large cells grow, an insight that could one day provide insight into attacking diseases such as cancer.
Probing the Forces Involved in Creating The Mitotic Spindle
Scientists at The Rockefeller University reveal new insights into the mechanical forces that govern elements of the mitotic spindle formation.
Identifying Cancer’s Food Sensors May Help to Halt Tumour Growth
Oxford University researchers have identified a protein used by tumours to help them detect food supplies. Initial studies show that targeting the protein could restrict cancerous cells’ ability to grow.
Specific Variations in RNA Splicing Linked to Breast Cancer
Researchers have identified cellular changes that may play a role in converting normal breast cells into tumors. Targeting these changes could potentially lead to therapies for some forms of breast cancer.
Thousands of Protein Interactions Identified
Thanks to the work by Utrecht University researcher Fan Liu and her colleagues, it is now possible to map the interactions between proteins in human cells.
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
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos