Mutations in KRAS, HRAS, and NRAS are common drivers of lethal cancers. RAS must be anchored to the inside of cell membranes to work. This attachment to the membrane allows RAS proteins to organize into complexes. Raf kinases and other signaling proteins add to RAS complexes to form larger complexes that efficiently signal to regulate important cellular processes.

The structures of these complexes are poorly understood and hard to study because they are short-lived. The Westover lab has published evidence, including biological validation, for two structural models of RAS complexes, including a symmetric RAS model and an asymmetric model. We believe these structures have unique functions in c...

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Mutations in KRAS, HRAS, and NRAS are common drivers of lethal cancers. RAS must be anchored to the inside of cell membranes to work. This attachment to the membrane allows RAS proteins to organize into complexes. Raf kinases and other signaling proteins add to RAS complexes to form larger complexes that efficiently signal to regulate important cellular processes.

The structures of these complexes are poorly understood and hard to study because they are short-lived. The Westover lab has published evidence, including biological validation, for two structural models of RAS complexes, including a symmetric RAS model and an asymmetric model. We believe these structures have unique functions in cells.

This proposal will seek to clarify the biological functions of these structures including how cancer causing mutations in HRAS and NRAS may influence the structures of RAS complexes to cause cancer. We will work to discover specific RAS mutants that induce structures that are targetable by known small molecule inhibitors such as Raf and MEK inhibitors. Successful completion of this goal will yield biomarkers that predict for RAS-mutated cancer sensitivity to Raf and MEK inhibitors. Finally we will develop methods, including cutting edge methods that let us directly observe RAS complexes, to identify new inhibitors that can alter the structure of RAS-containing complexes.

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