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Trastuzumab-induced phosphorylation of pY 1248-ErbB2 site is associated with suppression in Akt signaling

Wednesday, October 10, 2012 — Poster Session II

Noon – 2:00 p.m

Natcher Conference Center, Building 45




  • M. Dokmanovic
  • D.S. Hirsch
  • M.K. ElZarrad
  • Y. Shen
  • W.J. Wu


Trastuzumab is a humanized monoclonal antibody generated against the ErbB2 receptor and is approved for the treatment of ErbB2 positive metastatic breast cancer. ErbB2 homodimerization or heterodimerization with either ErbB1 or ErbB3 can result in the activation of PI3K or MAPK signaling pathways. The mechanisms by which trastuzumab suppresses the activity of PI3K pathway are still incompletely understood. Our results indicate that trastuzumab binding to ErbB2 is associated with induction in ErbB2 phosphorylation at pY-1248, induction in ErbB1 phosphorylation at pY-845, reduction in ErbB3 phosphorylation at 1289 and reduction at Akt Ser 473 phosphorylation. Pretreatment of SKBR3 cells with Lapatinib, an inhibitor of ErbB1 and ErbB2 kinase, while abolishing trastuzumab induced phosphorylation at ErbB1 pY 845 did not abrogate trastuzumab induced ErbB2 pY 1248 phosphorylation. This suggests that trastuzumab mediated ErbB2 phosphorylation at pY 1248 is, at least in part, ErbB1/2 kinase independent. Identification of the molecular mechanisms by which trastuzumab binding promotes induction of ErbB2 pY1248 phosphorylation, while suppressing PI3K pathway signaling, may elucidate a novel mechanism of trastuzumab action. Disclaimer: The information presented in this abstract reflects the views of the authors and does not necessarily represent the policy of the U.S Food and Drug Administration

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