New idea for targeting the common cancer protein KRAS

October 20, 2013

Patients with cancers driven by the protein KRAS, which are particularly hard to treat, may benefit from small molecules that attach to and disrupt the function of a KRAS-containing protein complex, according to results presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held Oct. 19-23.

Mutant forms of the protein KRAS are found in approximately 30 percent of all cancers. They are responsible for many of the hallmarks of these cancers, and KRAS is, therefore, considered an important . However, attempts to develop clinically useful KRAS-targeted drugs have been unsuccessful.

"KRAS is a molecular switch," said Michael Burns, a doctor of medicine and doctor of philosophy candidate at Vanderbilt School of Medicine in Nashville, Tenn. "In the 'on' state it transmits signals that drive cell growth and survival. In many cancers, KRAS is permanently in the on state, and it is a highly validated therapeutic target.

"KRAS switches from off to on most efficiently when it is attached to a protein called SOS," explained Burns. "Each SOS attaches to two KRAS proteins, and we have identified a number of small molecules that bind to a particular part of SOS when it is in a complex with two KRAS proteins. These small molecules disrupt the function of the complex, ultimately causing inhibition of the signaling pathways downstream of KRAS that drive cell growth and survival. Although our data were generated in biochemical assays and , they suggest a potential way to therapeutically target KRAS, which has not been possible to date."

KRAS switches from off to on during a process called guanine nucleotide exchange, and SOS increases the rate at which this process occurs. Burns and colleagues hypothesized that small molecules that blocked SOS-mediated guanine nucleotide exchange would prevent KRAS switching on and, therefore, inhibit the signaling pathways downstream of KRAS that drive and survival.

Instead, they found that a number of small molecules that attached to a special pocket in a region of SOS called the CDC25 domain and increased SOS-mediated guanine nucleotide exchange actually inhibited two of the major signaling pathways downstream of KRAS: the MAPK and PI3K signaling pathways.

The researchers are actively investigating why small molecules that increased SOS-mediated guanine nucleotide exchange in biochemical assays blocked signaling downstream of KRAS in cell lines. They are also working to optimize the before they conduct studies in preclinical models of cancer.

Explore further: Scientists identify possible KRAS downstream target for pancreatic cancer therapy

More information: Abstract Number: C209/PR01
Presenter: Michael Burns

Title: Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange

Authors: Michael Burns1, Qi Sun1, Richard Daniels2, J. Phillip Kennedy1, DeMarco Camper1, Jason Phan1, Edward Olejniczak1, Taekyu Lee1, Alex Waterson1, Olivia Rossanese1, Stephen Fesik1. 1Vanderbilt University School of Medicine, Nashville, TN; 2Lipscomb University, Nashville, TN

Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active receptor tyrosine kinases (RTKs) results in the deregulation of cellular signals governing growth and survival in cancer. The guanine nucleotide exchange factor Son of Sevenless (SOS) catalyzes the rate-limiting step in the activation of Ras by exchanging GDP for GTP. SOS is therefore a key control point for the propagation of RTK and Ras signaling. Here we report the discovery of small molecules that bind to a unique pocket on the Ras:SOS:Ras complex, increase SOScat-catalyzed nucleotide exchange, and perturb Ras signaling pathways in cells. X-ray crystallographic studies of Ras:SOS:Ras complexed with these small molecules reveal that they bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of the x-ray structures of multiple co-complexes. In addition, structure-based mutational analyses indicate that this newly identified pocket is essential for compound activity. As predicted, these molecules increase Ras-GTP levels in cells. However, they unexpectedly inhibit MAPK and PI3K signaling. Our studies suggest a novel way to target K-Ras and offer possible starting points for the discovery of compounds that could be used to treat Ras-driven tumors.

Related Stories

Scientists identify possible KRAS downstream target for pancreatic cancer therapy

May 28, 2013
While the mutated KRAS oncogene is associated with many cancers, it has not yet been successfully targeted by a therapeutic agent. Scientists are trying to find another way to target the gene by blocking signals from another ...

Combination therapies for drug-resistant cancers

October 10, 2011
Some cancers can be effectively treated with drugs inhibiting proteins known as receptor tyrosine kinases, but not those cancers caused by mutations in the KRAS gene. A team of researchers led by Jeffrey Engelman, at Massachusetts ...

KRAS gene mutation and amplification status affects sensitivity to antifolate therapy

April 4, 2012
Testing patients with non-small cell lung cancer for both mutations and amplifications of the KRAS gene prior to therapy may help to predict response to treatment with antifolates, according to the updated results of a preclinical ...

New inhibitor blocks the oncogenic protein KRAS

August 9, 2013
One of the major goals in the development of anti-cancer treatments is to find an inhibitor effective against the oncogenic protein known as KRAS. Despite decades of active agent research, efforts to intercede in this protein's ...

Antifolates show promise against NSCLC subtype

November 14, 2011
Patients with non-small cell lung cancer who have mutations in the KRAS gene should respond well to the antifolate class of drugs, according to results of a recent study conducted by Quintiles comparing human lung cancer ...

Gene linked to pancreatic cancer growth, study finds

January 31, 2012
A mutant protein found in nearly all pancreatic cancers plays a role not only in the cancer's development but in its continued growth, according to a new study from University of Michigan Comprehensive Cancer Center researchers. ...

Recommended for you

Zebrafish larvae could be used as 'avatars' to optimize personalized treatment of cancer

August 21, 2017
Portuguese scientists have for the first time shown that the larvae of a tiny fish could one day become the preferred model for predicting, in advance, the response of human malignant tumors to the various therapeutic drugs ...

Searching for the 'signature' causes of BRCAness in breast cancer

August 21, 2017
Breast cancer cells with defects in the DNA damage repair-genes BRCA1 and BRCA2 have a mutational signature (a pattern of base swaps—e.g., Ts for Gs, Cs for As—throughout a genome) known in cancer genomics as "Signature ...

Scientists discover vitamin C regulates stem cell function, curbs leukemia development

August 21, 2017
Not much is known about stem cell metabolism, but a new study from the Children's Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then ...

How a non-coding RNA encourages cancer growth and metastasis

August 21, 2017
A mechanism that pushes a certain gene to produce a non-coding form of RNA instead of its protein-coding alternative can promote the growth of cancer, report researchers at the Medical University of South Carolina (MUSC) ...

Spaser can detect, kill circulating tumor cells to prevent cancer metastases, study finds

August 21, 2017
A nanolaser known as the spaser can serve as a super-bright, water-soluble, biocompatible probe capable of finding metastasized cancer cells in the blood stream and then killing these cells, according to a new research study.

Comprehensive genomic analysis offers insights into causes of Wilms tumor development

August 21, 2017
A comprehensive genomic analysis of Wilms tumor - the most common kidney cancer in children - found genetic mutations involving a large number of genes that fall into two major categories. These categories involve cellular ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.