FCCC LOGO Faculty Publications
RASpecting the oncogene: New pathways to therapeutic advances
Biochem Pharmacol. 2018 Dec;158 :217-228
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RAS is the most commonly mutated driver of tumorigenesis, seen in about 30% of all cancer cases. There is a subset of cancers termed RAS-driven cancers in which RAS mutation or overactivation is evident as much as 95% in pancreatic and 50% in colon cancer. RAS is a family of small membrane bound GTPases that act as a signaling node to control both normal and cancer biology. Since the discovery of RAS' overall prominence in many tumor types and specifically in RAS-dependent cancers, it has been an obvious therapeutic target for drug development. However, RAS has proved a very elusive target, and after a few prominent RAS targeted drugs failed in clinical trials after decades of research, RAS was termed "undruggable" and research in this field was greatly hampered. An increase in knowledge about basic RAS biology has led to a resurgence in the generation of novel therapeutics targeting RAS signaling utilizing various and distinct approaches. These new drugs target RAS activation directly, inhibit downstream signaling effectors of RAS and inhibit of proper post-translational processing and trafficking/recycling of RAS. This review will cover how these new drugs were developed and how they have fared in pre-clinical and early phase clinical trials.
1873-2968 Stout, Matthew C Campbell, Paul M Journal Article Review England Biochem Pharmacol. 2018 Oct 20. pii: S0006-2952(18)30443-X. doi: 10.1016/j.bcp.2018.10.022.