Members of the Sprouty (Spry) gene family encode novel proteins that function as intracellular antagonists of the Ras signaling pathway. Loss of Spry function would be predicted to enhance Ras signaling.
Several mechanisms appear to increase Ras signaling in the most common type of human lung cancer, non-small cell lung cancer (NSCLC). Epidermal growth factor receptor members and/or one of their ligands are expressed in most NSCLCs. Similarly, fibroblast growth factor 2 is expressed in many NSCLCs, if not most. Alternatively, 15 to 20% of NSCLCs have activating mutations in the KRAS gene. It remains unclear what role Ras signaling may play in the pathogenesis of NSCLC, but at least one consequence appears to be increased proliferation. In a mouse model of lung cancer, the chemical carcinogen urethane causes activating mutations in K-ras and induces lung tumors. Thus, perturbations that would be predicted to enhance Ras signaling appear to play a key role in the pathogenesis of some types of NSCLC. Such perturbations also appear to be markers of a more biologically aggressive cancer since patients with these tumors do worse.