Mutations in the neuroblastoma rat sarcoma viral oncogene (NRAS) play an important role in cancer. NRAS mutations are found in 15-20% of malignant melanomas, but also in several other cancer types. These point mutations usually affect codons 12, 13 (Exon I) and 61 (Exon II) of the NRAS gene. The mutant NRAS protein constitutively activates downstream signaling cascades such as the MAPK, PI3K/AKT/mTOR and Ral pathways, resulting in uncontrolled cell proliferation and tumor growth. Attempts to directly inhibit mutant NRAS have been unsuccessful so far. Treatment approaches use small molecule inhibitors which interfere with NRAS downstream pathways. Mitogen-activated protein kinase kinase (MEK) inhibitors block signaling through the MAPK pathway and NRAS mutated tumors are associated with MEK inhibitor efficacy. The MEK inhibitor trametinib has shown clinical efficacy in patients with NRAS mutant cancers.
Vujic I, Sanlorenzo M, Posch C, et al. Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. Oncotarget. 2015;6(2):969-978.