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Extracellular Domain Mutations in EGFR Occur Uniquely in Glioblastoma and Favor Ligand-Independent Formation of the Active State Susan L. McGovern, Marta L. Rojas, Anupama Gururaj, Wah Chiu, Oliver Bogler, and John N. Weinstein Departments of Radiation Oncology, Neurosurgery, and Biostatistics MD Anderson Cancer Center Department of Biochemistry Baylor College of Medicine Houston, TX ASTRO 2012
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What is the pattern of missense mutations in EGFR in glioblastoma?
Cancer COSMIC Extracellular missense mutations in EGFR Intracellularmissense mutations in EGFR Lung adenoca 2282 Lung SCC 38 Lung BAC 48 Ovarian 18 Head & neck 19 Mesothelioma 9 Prostate 29 Thyroid 15 Glioblastoma 68 8 Cancer COSMIC Extracellular missense mutations in EGFR Intracellularmissense mutations in EGFR Lung adenoca 2282 Lung SCC 38 Lung BAC 48 Ovarian 18 Head & neck 19 Mesothelioma 9 Prostate 29 Thyroid 15 Cancer COSMIC TCGA Validation Set Extracellular missense mutations in EGFR Intracellularmissense mutations in EGFR Lung adenoca 2282 Lung SCC 38 Lung BAC 48 Ovarian 18 Head & neck 19 Mesothelioma 9 Prostate 29 Thyroid 15 Glioblastoma 68 8 35 1 What is the pattern of missense mutations in EGFR in glioblastoma? Describe Cosmic and TCGA p <
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Structure of EGFR monomer (1NQL) Structure of EGFR dimer (3NJP)
21 missense mutations (A289V/D/T) 14 missense mutations (G598V) 7 missense mutations (R108K) 4 missense mutations (T263P) 2 missense mutations (R324L, P596L, C620W/Y) 1 missense mutation (16 residues) I II III IV EGF III IV II I Label domains in dimer; have structure of EGF binding; based on looking at mutations, what do you learn? Many in domian I; many also along dimer interface; many also in domain 4, near membrane and also near domai; many of these mutations would interfere with domain-domain interactions or dimer-interface, not predictable from sequence; lesson #1: this was not obvious from the sequence!!! extracellular intracellular
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Point mutants show increased phosphorylation in the absence of EGF.
R108K T263P A289D A289T EGFRvIII EGFR 1726-zeo Relative Phosphorylation Y1068 Serum starved Y845 Serum starved EGF EGF Relative Phosphorylation R108K T263P A289D A289T EGFR EGFRvIII 1726-zeo Point mutants show increased phosphorylation in the absence of EGF. Bogler lab, MDACC
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Point mutations have worse survival than wt EGFR.
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. Xenograft Median survival (d) p-value vs. wt EGFR p-value vs. EGFR vIII wt EGFR 16 --- 0.0001 EGFR vIII 13 R108K 0.0017 0.06 T263P 17 0.068 A289D 14 0.03 0.0005 A289T 0.012 Bogler lab, MDACC
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R108K: loss of hydrogen bonds A289T: pulling open latch?
A289D R108 E84 A289T R108 E84 A289 A289 R108K E84 A289 R108 E84 III IV I II Label domains; R108K: loss of hydrogen bonds A289T: pulling open latch? A289D: pulling open latch? wild type EGFR
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Model for A289T/D or R108K wt EGFR 95% 5% A289V or R108K
I II III IV E I II III IV E I III IV II 95% 5% A289V or R108K I III II IV I III IV II Adapted from Li, et al. Cancer Cell (2005)
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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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