Stick It To RAS: The Next Wave Of RAS Therapeutics


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. 

Also included in this newsletter:

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