title: De-repression of PDGFRβ transcription promotes acquired resistance to EGFR tyrosine kinase inhibitors in glioblastoma patients.
abstract: Acquired resistance to tyrosine kinase inhibitors (TKI) represents a major challenge for personalized cancer therapy. Multiple genetic mechanisms of acquired TKI resistance have been identified in several types of human cancer. However, the possibility that cancer cells may also evade treatment by co-opting physiologically regulated receptors has not been addressed. Here, we show the first example of this alternate mechanism in brain tumors by showing that EGF receptor (EGFR)-mutant glioblastomas (GBMs) evade EGFR TKIs by transcriptionally de-repressing platelet-derived growth factor receptor β (PDGFRβ). Mechanistic studies show that EGFRvIII signaling actively suppresses PDGFRβ transcription in an mTORC1- and extracellular signal-regulated kinase-dependent manner. Genetic or pharmacologic inhibition of oncogenic EGFR renders GBMs dependent on the consequently de-repressed PDGFRβ signaling for growth and survival. Importantly, combined inhibition of EGFR and PDGFRβ signaling potently suppresses tumor growth in vivo. These data identify a novel, nongenetic TKI resistance mechanism in brain tumors and provide compelling rationale for combination therapy.
  
  
  CONCLUSIONS
  These results provide the fi rst clinical and biologic evidence for receptor tyrosinekinase (RTK) "switching" as a mechanism of resistance to EGFR inhibitors in GBM and provide a molecular explanation of how tumors can become "addicted" to a non amplified, nonmutated, physiologically regulated RTK to evade targeted treatment.
authors.affiliation: Medical Scientist Training Program, David Geffen School of Medicine
authors.forename: David
authors.initials: D
authors.lastname: Akhavan
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Pourzia
authors.forename: Alex A
authors.initials: AA
authors.lastname: Nourian
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.forename: Ivan
authors.initials: I
authors.lastname: Babic
authors.forename: Genaro R
authors.initials: GR
authors.lastname: Villa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ali
authors.initials: A
authors.lastname: Nael
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.forename: Julie
authors.initials: J
authors.lastname: Dang
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Mitchell
authors.initials: M
authors.lastname: Flagg
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Tamanoi
authors.forename: Takashi
authors.initials: T
authors.lastname: Sasayama
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Harley I
authors.initials: HI
authors.lastname: Kornblum
authors.forename: Tim F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000077341:Lapatinib; D020935:MAP Kinase Signaling System; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077341:Lapatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta