title: A Rational Approach to Target the Epidermal Growth Factor Receptor in Glioblastoma.
abstract: Glioblastoma (GBM) is a deadly brain cancer, and all attempts to control it have failed so far. However, the future looks bright, as we now know the molecular landscape of GBM through the work of The Cancer Genome Atlas (TCGA) program. GBMs exhibit significant inter- and intratumoral heterogeneity, and to control this type of tumor, a personalized approach is required. One target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But all attempts to target it have been unsuccessful. We attribute the reason for this failure to the molecular heterogeneity of EGFR in GBM, as well as to the poor brain penetration of previously tested EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs). In this review, we discuss the molecular heterogeneity of EGFR and provide rational preclinical and clinical guidelines for testing AZD9291, a third generation, irreversible EGFR-TKI with both a high affinity for EGFRvIII and excellent brain penetration.
authors.affiliation: Duke University Medical Center, Durham, P.O. Box 3094, NC 27710, United States.
authors.forename: Madan M
authors.initials: MM
authors.lastname: Kwatra
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; C410723:epidermal growth factor receptor VIII; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human
keywords: EGFR; Glioblastoma; TCGA; heterogeneity; targeted; therapies