title: Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma.
abstract: BACKGROUND
  The highly divergent histological heterogeneities, aggressive invasion and extremely poor response to treatment make glioblastoma (GBM) one of the most lethal and difficult cancers in humans. Among key elements driving its behavior is epidermal growth factor receptor (EGFR), however, neither traditional therapy including neurosurgery, radiation, temozolomide, nor targeted EGFR therapeutics in clinic has generated promising results to date. Strategies are now focusing on blocking the downstream EGFR-activated metabolic pathways and the key phosphorylated kinases.
  
  
  METHODS
  Here, we review two major EGFR-activated downstream metabolic pathways including the PI3K/AKT/mTOR and RAS/RAF/MAPK pathways and their key phosphorylated kinase alterations in GBMs. This review also discusses potential pharmacological progress from bench work to clinical trials in order to evaluate specific inhibitors as well as therapeutics targeting PI3K and RAS signaling pathways.
  
  
  CONCLUSIONS
  Several factors impede clinical progress in targeting GBM, including the high rates of acquired resistance, heterogeneity within and across the tumors, complexity of signaling pathways and difficulty in traversing the blood-brain barrier (BBB). Substantial insight into genetic and molecular pathways and strategies to better tap the potential of these agents include rational combinatorial regimens and molecular phenotype-based patient enrichment, each of which will undoubtedly generate new therapeutic approaches to combat these devastating disabilities in the near future.
authors.affiliation: Huazhong University of Science and Technology, Tongji Hospital, Tongji Medical College, Cancer Biology Research Center, wuhan, China.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors