| RAS GTPases are central transducers of signaling that mediates cell survival and proliferation fates. Mutations causing constituitive activity of RAS are found in ∼30% of all human cancers. Furthermore, many well characterized oncogenes function upstream of RAS, relying on RAS to relay oncogenic signals. Still others cooperate with RAS mutations to overcome checkpoints and contribute to malignant transformation of cells. Though RAS has been studied intensively for 40 years, targeted inhibition of oncogenic RAS has remained elusive. In the past decade focus has been on the development of Farnesyltransferase inhibitors, targeting a post-translational modification of RAS essential for its association with cellular membranes. These have not been as successful as hoped, however, due to a redundant mechanism of prenyl lipid modification at the same site by Geranylgeranyltransferase. Inhibition of both these enzymes has proved too toxic to be clinically practicable.;RAS undergoes further post-translational modifications, including cleavage of its carboxyl-terminus, methylation of the isoprenylated cysteine at this terminus, and for most isoforms, addition of palmitate at proximal cysteine(s). Certain RAS isoforms are often found associated with cancers arising from specific tissues. For hematological malignancies, NRAS is the isoform found most frequently, in ∼20--40% of all leukemias.;Here we examined the effects of inhibition of post-translational modifications on the ability of constituitively active NRAS to relay oncogenic signals and drive leukemia in vivo. We found that inhibition of RAS cleavage or methylation do not appear to be valid targets to disrupt oncogenic signaling by RAS, likely due to off target effects which enhance oncogenic transformation. However, using mutational disruption of the NRAS palmitoylation site, in conjunction with a murine retroviral transduction/bone marrow transplantation model, we found that palmitoylation is essential for NRAS leukemogenesis. We further found that disruption of NRAS palmitoylation also significantly delayed progression of BCR-ABL leukemias, demonstrating that inhibition of palmitoylation may be an effective target for oncogenes upstream of NRAS, greatly broadening the therapeutic potential of this target. These studies present a novel method of targeting RAS, a central oncogene in many cancers, and will optimistically lead to the development of new therapeutics to extend the lives of patients. |
