Grant: Project Grant

Human cells are shaped by their environment from the earliest stages of development. Cells must respond to environmental changes throughout their lifespan, coordinating a response with neighbouring cells and with those residing in far-away tissues. Millions of years of evolution have provided every cell with an ability to sense their surroundings and respond in an appropriate manner. Encoded by genes, the molecular machines that carry out these functions are called proteins. Each protein has a defined 3-dimensional shape that supports a unique function. Some proteins have evolved to alter their shape in response to a changing environment, and these play a prominent role in deciding cell fate. One such group of proteins, called GTPases, are often described as ON/OFF switches that coordinate whether cells grow, move or even die using an array of partner proteins specific for each task. Because of this important role, mutation of GTPases can be highly detrimental to human health. Indeed, the RAS GTPases are a leading driver of human cancers with nearly one third having mutations in RAS genes. These proteins have therefore become the leading target of cancer therapeutics, but a lack of treatments is why lung, colon, and pancreatic cancers have persistently high mortality rates. There are six highly similar RAS proteins in humans, but only three are commonly found mutated in cancer. How other RAS GTPases function or why they don't drive human cancers is unknown. We propose to fully understand how these switch-like proteins work and precisely determine why their response to environmental stimuli differs. Using multiple experimental approaches, we will study how RAS proteins evolved unique functions despite being extremely similar. This work will provide new therapeutic strategies to target RAS in cancer and is highly significant to patients, particularly those with malignant cancers such as pancreatic adenocarcinomas and lung NSCLCs.