Grant: Project Grant

Ras proteins are key regulators of cell division. Over a third of human cancers are associated with activating mutations in Ras genes, which makes them the most frequently mutated oncogenes. Pancreatic (90%), colorectal (50%), and lung (30%) cancers are particularly afflicted by Ras mutations. Despite intense efforts, there are still no approved drugs that directly curtail hyperactivated Ras. Significant progress has nonetheless recently been made through the development of inhibitors targeting proteins that convey Ras signals. My lab has a long-standing interest in a group of enzymes (RAF, MEK, and ERK) that mediates Ras signals in normal and cancer cells and is referred to as the ERK module. Inhibition of these proteins using small molecule inhibitors has been shown to block tumor growth. Although promising, current drugs exhibit nonetheless important adverse effects, including resistance and toxicity. One of our current interests is centered on the mechanism of RAF activation. RAF is the entry point in the ERK module. Its mechanism of activation is incompletely understood. We recently found that RAF activation depends on dimerization, whereby two RAF proteins contact each other enabling the mutual control of their activity. Intriguingly, this event confers resistance to RAF inhibitors in Ras-mutant cancer cells. In this application, we will investigate how RAF is kept autoinhibited in a monomeric form in non-stimulated cells. In addition, we will study how, upon stimulation, distinct RAF proteins dimerize together and thereby induce their activity. This work will provide an integrated picture of the mechanisms that govern RAF activity. In addition, it will identify novel points of entries in the Ras-ERK pathway that could be targeted with inhibitors for highly specific therapeutic purposes. RAF belongs to a class of enzymes known as kinases, of which several are influenced by dimerization. This work should also prove valuable to understand their regulation.