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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.

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Presentation on theme: "Extracellular Domain Mutations in EGFR Occur Uniquely in Glioblastoma and Favor Ligand-Independent Formation of the Active State Susan L. McGovern, Marta."— Presentation transcript:

1 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

2 Cancer COSMIC Extracellular missense mutations in EGFR Intracellular missense mutations in EGFR Lung adenoca02282 Lung SCC038 Lung BAC048 Ovarian018 Head & neck019 Mesothelioma09 Prostate029 Thyroid015 Glioblastoma688 Cancer COSMICTCGA Validation Set Extracellular missense mutations in EGFR Intracellular missense mutations in EGFR Extracellular missense mutations in EGFR Intracellular missense mutations in EGFR Lung adenoca02282 Lung SCC038 Lung BAC048 Ovarian018 Head & neck019 Mesothelioma09 Prostate029 Thyroid015 Glioblastoma Cancer COSMIC Extracellular missense mutations in EGFR Intracellular missense mutations in EGFR Lung adenoca02282 Lung SCC038 Lung BAC048 Ovarian018 Head & neck019 Mesothelioma09 Prostate029 Thyroid015 p < What is the pattern of missense mutations in EGFR in glioblastoma?

3 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) EGF Structure of EGFR monomer (1NQL)Structure of EGFR dimer (3NJP) extracellular intracellular I II III IV I II III IV

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

5 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 EGFR vIII R108K T263P A289D A289T Mice transfected with xenografts expressing point mutants or EGFR vIII.

6 A289T: pulling open latch?A289D: pulling open latch?R108K: loss of hydrogen bondswild type EGFR A289 R108K E84A289D R108 E84A289 R108 E84A289T R108 E84A289 R108 E84 I II III IV

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

8 Conclusions 1.In GBM, EGFR missense mutations preferentially occur in extracellular domain. 1.Many of these mutations may promote ligand-independent activation of EGFR. 2.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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