title: The RAS-RAL axis in cancer: evidence for mutation-specific selectivity in non-small cell lung cancer.
abstract: Activating RAS mutations are common in human tumors. These mutations are often markers for resistance to therapy and subsequent poor prognosis. So far, targeting the RAF-MEK-ERK and PI3K-AKT signaling pathways downstream of RAS is the only promising approach in the treatment of cancer patients harboring RAS mutations. RAL GTPase, another downstream effector of RAS, is also considered as a therapeutic option for the treatment of RAS-mutant cancers. The RAL GTPase family comprises RALA and RALB, which can have either divergent or similar functions in different tumor models. Recent studies on non-small cell lung cancer (NSCLC) have showed that different RAS mutations selectively activate specific effector pathways. This observation requires broader validation in other tumor tissue types, but if true, will provide a new approach to the treatment of RAS-mutant cancer patients by targeting specific downstream RAS effectors according to the type of RAS mutation. It also suggests that RAL GTPase inhibition will be an important treatment strategy for tumors harboring RAS glycine to cysteine (G12C) or glycien to valine (G12V) mutations, which are commonly found in NSCLC and pancreatic cancer.
authors.affiliation: 1] Department of Surgery, University of Colorado, Aurora, CO 80045, USA [2] Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Sunny
authors.initials: S
authors.lastname: Guin
authors.affiliation: 1] Department of Surgery, University of Colorado, Aurora, CO 80045, USA [2] Department of Pharmacology, University of Colorado, Aurora, CO 80045, USA [3] University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D020725:ral GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D020725:ral GTP-Binding Proteins; D018631:ras Proteins