Project 443419

Abnormal changes to the genetic material of various cell types in the human body can lead to cancer, or more specifically the uncontrolled proliferation of cells. When this occurs, the affected genes create proteins that cannot be turned off in a normal fashion. It is remarkable that mutations to one set of proteins, called RAS, are responsible for at least a quarter of all human cancers. A lack of effective therapies for RAS-driven cancers is the major reason why lung, colon, and pancreatic cancers remain the most refractory to available treatments. Of course, normal cells require these same proteins during development or in the process of healing a wound, to guide proliferation and such basic functions as attachment to other cells. To improve outcomes for patients we require significantly more research to understand all of the proteins connected to RAS in the cell, how they work in both normal and cancer cells, and to identify vulnerabilities that may be targeted by therapeutics. My team has developed new methods to study RAS function and its involvement with other proteins. Targeting these associations is finally proving effective in treating some cancers, yet important connections between RAS and many protein partners remain understudied. This includes proteins that regulate the ability of cells to attach or move, linked to metastasis, and proteins that lead to self-directed cell death. We use leading-edge techniques to gain insight to the three-dimensional shape of these proteins and complement our data with studies in cultured human cells or mice to observe how changes to these genes lead to cancer formation. We propose to identify and characterize new therapeutic targets in the vicinity of mutant RAS proteins, and these efforts will be complemented by the drug discovery capabilities at our institute. Our study has significance for many patients, particularly those with untreatable cancers such as pancreatic adenocarcinomas and lung NSCLCs.