For decades, researchers have known that about a third of all human cancers are driven by mutations in RAS genes. But blocking RAS-encoded proteins has, so far, been ineffective. The RAS protein family is involved in transmitting signals within cells, signals that result in growth and proliferation. When RAS genes are mutated, it may lead to overactive RAS signaling, leading cells to grow uncontrollably, even in the absence of incoming signals, and ultimately resulting in cancer. Those mutant RAS proteins are mostly of four different types: splice variants KRAS4A and KRAS4B, as well as HRAS and NRAS. But the complexity of the associated biology is such that clinical development of RAS-targeting drugs has been less than straightforward. “It's a system that is multiply redundant—otherwise we would die,” says Herbert Waldmann, director of the Max Planck Institute of Molecular Physiology, in Dortmund, Germany. The four RAS oncoproteins are part of a much larger superfamily of small GTPases, which regulate myriad cellular processes by modulating downstream signaling pathways. They function as molecular switches, cycling between active and inactive states by hydrolyzing guanosine nucleoside triphosphate (GTP) to GDP and by participating in nucleotide exchange (whereby a free GTP replaces a bound GDP). The switch has a slow cycle time, but it is accelerated by GTPase-activating proteins, which function as negative regulators of RAS activity by promoting GTP hydrolysis, and by guanine nucleotide exchange factors, which function as positive regulators of RAS activity by promoting RAS-GTP binding (Nat. Rev. Drug Disc. 13, 828–851, 2014). Oncogenic mutations cause the affected RAS proteins to become locked into a GTP-bound 'on' state, triggering downstream effector proteins to signal through pathways, such as RAF-MEK-ERK and PI3K-AKT, which promote cancer cell growth and survival.
RAS's picomolar affinity for GTP and GDP rules out the development of GTP-competitive inhibitors. It also lacks the deep hydrophobic pockets that drug hunters typically rely on to develop high-affinity binders to a protein. “Part of the reason people thought RAS was undruggable was it simply looks like a greasy ball—there's nothing to grab hold of,” says Channing Der, Kenan Distinguished Professor in the department of pharmacology at the University of North Carolina at Chapel Hill, North Carolina.
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