Panitumumab Inhibits EGFRvIII Activation in U87MG. Δ 2-7 Cells Whole cell lysates probe for total and phosphorylated EGFRvIII p-EGFR (Y1068) p-EGFR (Y1173) Total EGFR Panitumumab - + - +
c-Met Phosphorylation is Ligand Independent and Inhibited by Panitumumab but not AMG 102 U87MG Δ 2-7 cells were treated with different antibodies and c-met immunoprecipitated to determine levels of total and phosphorylated c-Met A549 + HGF (400 ng/ml) AMG102 (10 μ g/ml) Panitumumab (20 μ g/ml) Irrelevant Ab (30 μ g/ml) Combination (30 μ g/ml) Phospho c-Met Total c-Met
U87MG. Δ 2-7 Xenografts Treated with Panitumumab and AMG 102
Immunohistochemistry analysis of U87MG. Δ 2-7 xenografts treated with Panitumumab, AMG 102 or combination of both Xenografts were collected one day after second injection (mid-point of therapy) and analyzed for proliferation, blood vessels and apoptosis
Conclusions <ul><li>EGFRvIII activates multiple RTK’s </li></ul><ul><li>c-Met is activated by EGFRvIII in a ligand independent manner leading to resistance to AMG 102 </li></ul><ul><li>Panitumumab inhibits the EGFRvIII phosphorylation of c-Met and restores response to AMG 102 </li></ul><ul><li>EGFRvIII probably phosphorylates c-Met by direct interaction </li></ul><ul><li>Combination of Panitumumab and AMG 102 may be an effective therapy in GBM </li></ul>
Survival and Proliferation MAP-kinase Akt/PKB PI 3-kinase PIP 3 PDK1 MAP-kinase- kinase-kinase Ras Ras-GEF Grb2 PDGFR β EGFRvIII C-Met U87MG. Δ 2-7 Cells EGFRvIII co-activates other RTKs including c-Met
Survival and Proliferation MAP-kinase Akt/PKB PI 3-kinase PIP 3 PDK1 MAP-kinase- kinase-kinase Ras Ras-GEF Grb2 x x Panitumumab Xenografts partially inhibited by Panitumumab but can revert to the HGF/c-Met pathway
Survival and Proliferation MAP-kinase Akt/PKB PI 3-kinase PIP 3 PDK1 MAP-kinase- kinase-kinase Ras Ras-GEF Grb2 x x Xenografts inhibited by the combination of Panitumumab and AMG 102 x x
Acknowledgements Oncogenic Signalling Laboratory Vino Pillay Terri Burgess, Angela Coxen and Kelly Oliner Amgen Inc.
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