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p < 10 -100

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  1. Extracellular Domain Mutations in EGFR Occur Uniquely in Glioblastoma and Favor Ligand-Independent Formation of the Active StateSusan L. McGovern, Marta L. Rojas, AnupamaGururaj, WahChiu, Oliver Bogler, and John N. WeinsteinDepartments of Radiation Oncology, Neurosurgery, and BiostatisticsMD Anderson Cancer CenterDepartment of BiochemistryBaylor College of MedicineHouston, TXASTRO 2012

  2. What is the pattern of missense mutations in EGFR in glioblastoma? p < 10-100

  3. Structure of EGFR monomer (1NQL) Structure of EGFR dimer (3NJP) II I III IV III EGF II I 21missense mutations (A289V/D/T) 14missense mutations (G598V) 7missense mutations (R108K) IV 4missense mutations (T263P) 2missense mutations (R324L, P596L, C620W/Y) 1missense mutation (16 residues) extracellular intracellular

  4. Y845 Serum starved Serum starved EGF EGF Relative Phosphorylation Y1068 Relative Phosphorylation EGFR T263P A289D A289T R108K 1726-zeo EGFRvIII Point mutants show increased phosphorylation in the absence of EGF. EGFR T263P A289D A289T R108K 1726-zeo EGFRvIII Bogler lab, MDACC

  5. Mice transfected with xenografts expressing point mutants or EGFR vIII. Point mutations have worse survival than wt EGFR. Point mutants have better survival than EGFR vIII. Bogler lab, MDACC

  6. III R108 R108 R108 R108 R108K IV A289T A289 A289 A289D A289 E84 E84 E84 E84 E84 I II A289D: pulling open latch? wild type EGFR R108K: loss of hydrogen bonds A289T: pulling open latch?

  7. Model for A289T/D or R108K wt EGFR E 95% 5% A289V or R108K E E III III I I I I I I I I I II II II II II II E II II II III III III III III III III IV IV IV IV IV IV IV IV IV IV IV Adapted from Li, et al. Cancer Cell (2005)

  8. Conclusions • In GBM, EGFR missense mutations preferentially occur in extracellular domain. • Many of these mutations may promote ligand-independent activation of EGFR. • Better understanding of the biophysical and cellular consequences of these mutations may help identify subgroups of glioblastoma patients that may benefit from EGFR inhibitors (+ other therapies?)

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