Grant: Foundation Grant

RAS proteins are key regulators of cell division. Significantly, over a third of human cancers are associated with activating mutations in RAS genes, which makes them the most frequently mutated oncogenes. Yet, despite considerable efforts, there are still no approved drugs that suppress directly hyperactive RAS. Important advances have nonetheless been made in recent years by targeting RAS effector proteins. My lab has a long-standing interest in a group of proteins (RAF, MEK, and MAPK) that transmit RAS signals in normal and cancer cells. Markedly, inhibition of these proteins by pharmacological means curtails tumor growth. While this path has yielded some clinical successes, severe limitations emerged, including drug resistance and toxicity. We recently brought to light a central mechanism underlying RAF activation by RAS, which contributes in part to resistance to RAF inhibitors. We propose to extend our understanding of this mechanism and, based on learned principles, develop new classes of RAF inhibitors to evade drug resistance. Innovative strategies to directly inhibit RAS function will be also explored. Using the fruit fly model organism, we also found unexpected mechanisms that selectively control MAPK protein levels. We will study these mechanisms to identify novel means to manipulate RAS-MAPK activity. Given the high degree of evolutionary conservation of the pathway, these mechanisms will also be studied in human cells as they will provide alternative entry points for therapeutic intervention. Cancer research is a long and intricate process and it is only through multi-pronged approaches that valuable therapies will emerge. We have generated knowledge, tools, and partnerships with other groups that place us in a unique position to make major contributions to the cancer field. Given the high incidence of RAS-MAPK dependent cancers, we expect that efficacious compounds targeting this critical pathway will bring enormous benefits to human health.