Clinical Importance of Ras Proteins

Ras proteins are small GTPases that act as molecular switches to turn on and off diverse signaling pathways including those that are important for cell proliferation and survival. Ras proteins are active when bound to GTP and inactive when bound to GDP. Dysregulation of Ras activity can lead to abnormal cell proliferation and cancer.


More than 30% of all human cancers are driven by mutant Ras proteins that increase Ras activity (“activating mutations”). There are three Ras genes in humans: HRAS, KRAS, and NRAS. Activating KRAS mutations occur commonly in many cancers, especially pancreatic, colorectal, and lung cancers.  KRAS mutations account for about one million cancer deaths per year worldwide. NRAS mutations tend to occur in acute myeloid leukaemia and melanoma, and HRAS mutations are not uncommonly found in bladder cancer.





The McCormick Lab research can be broadly categorized in to three main research themes: (i) directly targeting Ras proteins; (ii) indirectly modulating Ras protein activity by targeting its regulators or effectors; and (iii) developing tools, techniques and approaches to drive the above research in new directions.


New Ways of Directly Targeting Ras in Cancers

Unfortunately, cancers driven by KRAS mutations are not only common but also very difficult to treat. Currently no therapies exist that target KRAS directly. Conventional methods for directly disrupting KRAS function have failed for two major reasons; i) KRAS is an extremely smooth protein and does not contain apparent pockets or active sites that can be exploited for binding drugs, ii) GTP and GDP bind extremely tightly to the protein making it difficult to identify or design drugs that are effective competitive inhibitors.

The McCormick Lab is using cutting edge technologies to directly target KRAS, and the other Ras proteins. These approaches include using Proteolysis Targeting Chimeric Molecules (PROTACs), which use a ligand to target KRAS for ubiquitination and proteasomal degradation; and a collaboration with Biodesy Inc. to screen for small molecules that cause allosteric changes in KRAS.


Discovering Novel Indirect Targets for Disrupting Ras Regulation and Activity in Cancer

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Ras proteins are part of a complex and highly interconnected signaling network about which a lot is known but much more needs to be discovered. Developing indirect methods of targeting KRAS by disrupting upstream Ras regulators and downstream effectors has proved challenging. The network provides many opportunities for mutant Ras proteins to bypass pathways that are inhibited by drugs and for redundant mechanisms to kick-in and negate drug effects.






The McCormick lab has made a major commitment to characterizing the Ras signaling network including both Ras upstream regulators and effector pathways. Our research led to the discovery of the Ras GAP family of enzymes, one of which is the protein neurofibromin. We demonstrated that neurofibromin is a negative regulator of Ras and its loss leads to hyperactivation of Ras. We are continuing to investigate the regulation of neurofibromin and its interaction with proteins such as SPRED1, and how this pathway contributes to neurofibromatosis. More recently, we discovered KRAS specific suppression of non-canonical Wnt signaling, and are developing strategies to interrupt this pathway.




Developing New Technologies, Tools, and Approaches

New technologies and tools are needed to push the frontier in both of the above research directions. The McCormick lab is helping to develop and characterize new tools that will not only benefit our lab but all scientists pursuing Ras research.

We are developing chemical tools (based on hits from small molecule screens) to examine the regulatory role of Ras on downstream effectors by selectively targeting Ras in cell line models. It is hoped that these chemicals will be able to be used generally, to quickly and specifically dissect molecular pathways, and that some may become lead compounds for drug development.

We are collaborating with the NCI Ras Initiative to characterize a new set of cell lines. The mouse embryonic fibroblast (MEF) cell lines each contain only one Ras protein type: wild type or mutant N, H or KRAS. These cell lines are an extraordinarily powerful tool for examining the unique effects of each wildtype and mutant Ras protein on cell physiology. We are already using them to compare the effects of Ras proteins on cell metabolism and to characterize the effect of candidate drugs on each protein.

Lastly, but no less importantly, we are also taking a broad view of cancer cell metabolism and survival that extends beyond Ras specific pathways. Research in the lab is examining the pathways that mediate cancer cell heterogeneity and persistence, which is important for chemoresistance and cancer relapse.