title: Molecular pathways: the basis for rational combination using MEK inhibitors in KRAS-mutant cancers.
abstract: Mutations in RAS oncogenes are frequently observed in human cancers, and the mutations result in activation of the RAS-RAF-MEK-ERK pathway, leading to cell proliferation and survival. The pathway is, therefore, a potent therapeutic target in the RAS-mutant cancers. MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the RAS-mutant cancers. As RAS proteins activate other downstream signaling proteins in addition to the RAS-RAF-MEK-ERK pathway, combination therapeutic approaches with MEK inhibitors are also being evaluated. Moreover, MEK inhibitors can arrest cancer cells in G1 phase and repress prosurvival Bcl2 family proteins such as MCL1 and BCL2/BCLXL, and increase expression of Bim, a proapoptotic BH3-only family protein. This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors. A better understanding of the pathway will help us with development of rational combinations for the treatment of the RAS-mutant cancers.
authors.affiliation: Department of Medical Oncology;
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Okumura
authors.affiliation: Department of Medical Oncology; Lowe Center for Thoracic Oncology; and Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts pasi_janne@dfci.harvard.edu.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins