Stick It To RAS: The Next Wave Of RAS Therapeutics

Introduction

The small GTPase RAS protein is a critical molecular switch that cycles between GTP-bound (active) and GDP-bound (inactive) states.  Over the last 40 years, it has garnered significant interest because 1) It regulates several critical growth and proliferation signaling pathways, 2) has been identified as a key oncogenic driver, and 3) is one of the most highly mutated cancer genes, with nearly 19% of all cancers patients having a mutation in one of the 3 RAS isoforms (H-RAS, N-RAS, and K-RAS) ^{(reviewed in 1)}.  Yet, for much of the last 40 years, RAS was deemed undruggable due to its “smooth” surface with no obvious drug-binding features.

In 2021, that changed when work pioneered by the Shokat group² led to the first approved KRAS targeting drugs, sotorasib and adagrasib.  These drugs function by covalently binding to GDP-bound KRAS-G12C mutants.  The impact of this scientific breakthrough has been twofold – 1) in the clinic where it has had a tremendous impact on KRAS-G12C-dependent cancers and 2) it has muted the idea That KRAS is an undruggable target.  Unfortunately, these drugs can’t target wild-type KRAS and other KRAS mutants, such as KRAS G12D which occurs at a higher rate than KRAS-G12C, for example ^{(reviewed in 3)}. Fortunately, several new RAS targeting approaches are in development, and this newsletter will discuss some of these technologies that may lead to the next generation of novel RAS therapeutics.