RAS - The Undruggable Target

blog banner : RAS - The Undruggable Target

Long-termed the “undruggable target”, RAS has recently recaptured the attention of cancer researchers. A new understanding of this target has once again reignited hopes of modulating it to tackle some of the most lethal cancers.

RAS proteins are members of the superfamily of small GTPases comprising over 150 members. Three human RAS genes (HRAS, KRAS and NRAS) encode four highly related RAS small GTPases (HRAS, KRAS4A, KRAS4B and NRAS). RAS proteins function as GDP-GTP regulated binary on-off switches, which regulate a diverse set of cytoplasmic signaling networks. In cancer and developmental disorders (RASopathies) activated mutant RAS proteins drive aberrant signal transduction, which cause and drive disease states.

RAS is the most frequently mutated oncogene family in cancer, occurring in the top three most lethal cancers in the US in 2016; lung, colorectal and pancreatic.

You can learn more about RAS oncoproteins in a comprehensive review written by Drs. Adrienne Cox, Channing Der and Kirsten Bryant, which is free to download.

RAS Review

Dr. Adrienne Cox is Associate Professor of Radiation Oncology and Pharmacology, whose laboratory studies RAS with a focus on RAS isoform and mutation-selective functions and regulators of RAS subcellular localization. Dr. Channing Der is Sarah Graham Kenan Professor of Pharmacology whose studies centre on drugging RAS effector signaling networks. Dr. Kirsten Bryant is a Postdoctoral Fellow in Dr. Der’s laboratory whose studies focus on exploiting the metabolic dependencies of RAS mutant cancers.

This review focuses on the vulnerabilities of RAS that have been targeted by RAS pharmacologic inhibitors, with a focus on RAS-dependent metabolic processes. Pharmacological modulators of RAS function are discussed in depth, including those that inhibit RAS directly, RAS membrane association and RAS effectors. Please feel free to contact us if you are looking for a RAS compound that is not featured in the review - we update our catalog with the latest research tools every week!

RAS pathway

RAS mutant cancer cells are characterized by increased macropinocytosis and uptake of albumin, leading to lysosomal degradation and release of amino acids. RAS mutant cancer cells also exhibit altered autophagy, leading to degradation of organelles and proteins, and production of amino acids and other components to support metabolism. Oncogenic KRAS directs glucose metabolism into biosynthetic pathways in pancreatic ductal adenocarcinoma (PDAC) by upregulating many key enzymes in glycolysis; as well as inducing nonoxidative pentose phosphate pathway (PPP) flux to fuel increased nucleic acid biosynthesis and activate the hexosamine biosynthesis and glycosylation pathways. PDAC cells also utilize a non-canonical pathway to process glutamine, through which it maintains redox balance and supports cell growth.

Blog Categories: