Accession Number:

ADA478663

Title:

Identification of the Her-2 Functional Site: Blockage of Receptor Heterodimerization

Descriptive Note:

Final rept. 10 Aug 2006-9 Aug 2007

Corporate Author:

EVANSTON NORTHWESTERN HEALTHCARE RESEARCH INST IL

Personal Author(s):

Report Date:

2007-09-01

Pagination or Media Count:

15.0

Abstract:

Targeting HER2 is not as straightforward as it was originally predicted since many breast tumors express multiple HER receptors and co-express one or more HER ligands. This cross-talk network negatively impacts the response to the currently used HER2-targeted agents, highlighting the urgent need for a novel anti-HER2 molecules presenting a combination strategy. Activation of the HER2 receptor is attained by several means 1 receptor overexpression leads to homodimerization 2 EGF induces EGFR-HER2 hetero-dimerization by binding to EGFR and inducing HER2 activation via crosstalk and 3 Heregulin HRG induces HER3-HER2 hetero-dimerization by activating HER2 via its binding to the HER3 and HER4 receptors, in turn inducing receptor crosstalk and activation of a signaling cascade. In short, our preliminary study reveals that the specific disruption of an essential activating sequence existing on HER2 ECD domain III is capable of disabling the HER2 homo- and hetero-dimerization, thus blocking activation of HER2-driven oncogenic signaling and generating a dominant-negative Peptides or compounds with specificity for this functional site should add a previously unrecognized molecular approach to our therapeutic arsenal for the management of HER2-overexpressing carcinomas.

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE