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Journal of Pharmacology and Medicinal Chemistry

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Redox-dependent targeting of mutant RAS driven cancers

Author(s): Shazib Pervaiz

 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. We also provide evidence to implicate activation of Akt/PKB, downstream of mutant active KRAS, in triggering oxidative stress and autophagy associated cell death. These data and their potential implications for the design of novel therapeutic strategies to target mutant RAS driven cancers will be discussed. Recent Publications 1. Wong C H, Iskandar K B, Yadav S K, Hirpara J L, Loh T Pervaiz S (2016) Simultaneous induction of non- canonical autophagy and apoptosis in cancer cells by ROS-dependent ERK and JNK activation. PLoS One. 5(4):e9996. 2. Iskandar K, Rezlan M, Yadav S, Foo Chuan Han J, Sethi G, Qiang Y, Bellot G, Pervaiz S (2016) Synthetic lethality of a novel small molecule against mutant KRAS expressing cancer cells involves Akt dependent ROS production.