Targeting oncogenic Ras
- Department of Pediatrics, University of California, San Francisco, California 94143, USA
This extract was created in the absence of an abstract.
Reversing the consequences of oncogenic Ras is a fundamental problem in cancer therapeutics. Somatic RAS mutations are highly prevalent in many human cancers that respond poorly to current treatments, including carcinomas of the lung, pancreas, and colon; melanoma; and myeloid leukemia (for review, see Schubbert et al. 2007). At first glance, oncogenic Ras is an appealing target for rational drug discovery as the mutant protein is a membrane-associated signaling molecule that is expressed at robust levels in primary tumor cells. However, targeting oncogenic Ras is extremely challenging in practice due to the nature of the Ras cycle and the functional consequences of oncogenic mutations (for review, see Vetter and Wittinghofer 2001; Downward 2003). Ras relies on an intrinsic GTPase activity to terminate signaling by hydrolyzing GTP to GDP. This “off” reaction is relatively inefficient, but is accelerated thousands of fold by the GTPase-activating proteins (GAPs) neurofibromin and p120 GAP, which stabilize a transition state between Ras-GTP and Ras-GDP. Cancer-associated amino acid substitutions at codons 12, 13, and 61 both impair intrinsic Ras GTPase activity and confer resistance to GAPs. In principle, an effective small molecule therapy must therefore restore enzymatic activity within a highly constrained phosphate-binding loop of the oncoprotein without deregulating normal Ras or related cellular GTPases. Given these grim biochemical realities, drug discovery efforts have primarily focused in two areas: (1) blocking enzymes such as farnesyl transferase, which catalyze post-translational modifications of Ras that are essential for membrane targeting; and (2) developing inhibitors of downstream kinases such as MEK, Akt, and mTOR. Inherent in these strategies is the notion that reversing the growth of Ras-driven malignancies inevitably requires interrupting aberrant cell-intrinsic signaling networks. However, despite substantial effort, there are currently no agents that effectively counter the biochemical consequences of oncogenic Ras. A provocative paper by Ancrile et …
