The ability to selectively and directly target activated Ras would provide immense utility for treatment of the numerous cancers that are driven by oncogenic Ras mutations. Patients with disorders driven by overactivated wild-type Ras proteins, such as type 1 neurofibromatosis, might also benefit from progress made in that context. Activated Ras is an extremely challenging direct drug target due to the inherent difficulties in disrupting the protein:protein interactions that underlie its activation and function. Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials. Likely reasons for this disappointing outcome include the significant and underappreciated differences in the isoforms of Ras. It is still plausible that inhibition of farnesyl transferase will prove effective for disease that is driven by activated H-Ras. The principal current focus of drugs entering clinic trial is inhibition of pathways downstream of activated Ras, for example, trametinib, a first-in-class MEK inhibitor. The complexity of signaling that is driven by activated Ras indicates that effective inhibition of oncogenic transduction through this approach will be difficult, with resistance being likely to emerge through switch to parallel pathways. Durable disease responses will probably require combinatorial block of several downstream targets. 1. Introduction: Ras Activation and Cancer Ras proteins are key controllers of cellular growth and differentiation [1], with critical roles in the development [2, 3] and maintenance [4] of human tumors. As the prototypical small GTPase, Ras is regulated through an activation/deactivation cycle of exchange of GTP for GDP and subsequent GTP hydrolysis [5]. The GTP-bound state is the active conformation that can couple to downstream effectors [6]. The slow intrinsic rates of activation and deactivation of wild-type Ras allow catalytic control through exchange factors (GEFs) and GTPase-activating proteins (GAPs) [7]. Although acute decrease in GAP activity was the first mechanism described for agonist-induced Ras activation [8, 9], most instances of acute Ras activation are probably due to regulation of GEF activity [10, 11]. About 30% of human cancers have a mutated Ras protein [12] that is constitutively bound to GTP [13] due to decreased GTPase activity and insensitivity to GAP action [14–16]. Ras is also an important factor in many cancers where it is not mutated but rather functionally activated through inappropriate activity of
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