RAS family of GTPases is frequently mutated in human cancers. The current therapeutic strategies to target mutant RAS driven cancers rely mostly on inhibitors that either block the farnesylation/geranylation of RAS or inactivate effectors downstream of activated RAS, such as AKT, MEK and ERK. Despite these endeavors, the clinical outcome of patients harboring mutant RAS expressing cancers remain less than optimal. Our recent work highlights a novel strategy to overcome RAS addiction in human colorectal, pancreatic and non-small cell lung cancer that frequently carry RAS mutations. Exploiting the RAS specific activity of a novel small molecule compound, we provide evidence that hyper-activation of mutant KRAS-and not its inhibition-results in massive redox catastrophe culminating in mitochondrial short circuiting and death execution.
