In addition, frequent mutations in downstream RAS effectors have been reported, the most common of which check details is BRAF which has been reported to be mutated in approxi mately 50% of cases. Mutated BRAF can be effectively targeted in patients with metastatic melanoma, with impressive response rates in early phase trials. Recent data now demonstrates an improvement in overall survival in patients treated with selective BRAF inhibitors when compared to dacarbazine, although many patients ultimately relapse, further highlighting the importance of understanding the molecular pathogenesis of this disease. Activation of the PI3 Kinase/Akt pathway has also been implicated in melanoma tumorigenesis, potentially through downregulated expression of the negative regula tor PTEN.

Interestingly, even in melanoma cells having mutations in downstream effectors, constitutive RAS activation is nonetheless seen, likely through the ac tivity of autocrine or paracrine growth factor secretion. Transgenic mouse experiments have confirmed the important contribution of activated RAS based signaling to melanomagenesis in vivo. Targeted inhibition of RAS based signaling has there fore received significant attention. While kinase inhibi tors that interfere with the activity of the downstream molecules PI3 Kinase, RAF, and MEK are in various stages of development, it has been difficult to identify a pharmacologic strategy to inhibit RAS activity directly. However, the fact that RAS must undergo a lipid post translational modification for localization to mem brane compartments where access to its effectors occurs generated an alternative strategy for inhibiting RAS function.

The most important post translational modifi cation of RAS is farnesylation, which is catalyzed by the enzyme Farnesyltransferase. FT inhibitors have been developed as a strategy to block this process, thereby decreasing RAS translocation to mem branes and reducing its ability to mediate activation of downstream effectors. Interestingly, despite the ini tial motivation of FTI development driven by an interest in inhibiting RAS, FTIs have subsequently been shown to have effects on numerous additional proteins involved in tumor survival and proliferation. These include other GTPases such as Rheb, Ral, RhoC and Rac1, as well as factors involved in regulated protein translation and angiogenesis.

Preclinical data have shown anti proliferative activity that is independent of Ras mutation status, Anacetrapib and mechanistic experiments have implicated al ternative farnesylated targets as functionally relevant. Thus, FTIs may in fact target multiple signaling mole cules that contribute selleck compound to malignant transformation and are no longer viewed as pure RAS inhibitors. Re cently, there has also been evidence to suggest that FTIs may enhance the effectiveness of cytotoxic chemother apy when used in combination, potentially expanding the role of these agents.