Abstract
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.
Highlights
Ras Activation and CancerRas proteins are key controllers of cellular growth and differentiation [1], with critical roles in the development [2, 3] and maintenance [4] of human tumors
In the event that clinical situations can be identified where the Ras-driven signal may be predominantly through a single pathway, such as that through extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) that can be selectively blocked with mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors, there would presumably be high potential for resistance to develop via selection of a subclone that has oncogenic signaling through, for example, the PI 3-kinase/Akt pathway
The recognition that driving, oncogenic Ras mutations are prevalent in human cancer, together with the early studies that identified the molecular defect, gave promise that rationally designed, targeted therapeutics for a broad swath of cancers would follow
Summary
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. The Ras isoforms exhibit particular subcellular localizations [37, 38] that contribute both to the in situ selectivity of their activation and deactivation [39] and to isoform-specific downstream signaling [40] It is not entirely clear whether the limited biochemical and cell biological distinctions that are known to exist between these extremely similar proteins provide a full explanation for the striking functional differences found in the involvement of the isoforms in human disease or if there may be additional factors that are still to be elucidated. In addition to differences at the protein level it is possible that there could be significant isoform selectivity exerted through processes such as microRNA regulation [41,42,43]
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