ErbB receptor homo- and hetero-dimerization

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): The application is in response to Notice Number (NOT-OD-09-058): NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The four members of the ErbB family of receptor tyrosine kinases are important in many human cancers. Unfortunately, clinical studies with EGFR- and ErbB2-targeted agents in many cancers are very disappointing. Very recent work shows that ErbB3, a neuregulin (NRG) receptor with a kinase domain that is believed to be inactive, provides much of the explanation. Although ErbB2 signals to promote cell growth in the initiation and maintenance of cancers, it must form NRG-induced heterodimers with ErbB3 to do so. ErbB3 drives escape from ErbB2 and EGFR-targeted therapies in breast cancer. Thus, ErbB3 signaling is critical both for the role of ErbB2 (and EGFR) in cell signaling and for clinical failure of ErbB2 and EGFR-targeted therapies. Accordingly, it has been argued that targeting ErbB3 is a crucial therapeutic strategy - although progress is stymied by its apparent lack of kinase activity (leaving it unclear how to target the receptor). In very recent studies, we have shown that ErbB3 does have significant tyrosine kinase activity after all. The failure of previous studies to detect this activity reflects the relative lack of understanding of ligand-induced dimerization of ErbB receptors at the time those early reports were published. When activated correctly, purified ErbB3 is robustly autophosphorylated. This finding opens the door to therapeutic inhibition of an important kinase activity that was previously thought not to exist. We have also solved the ErbB3 kinase domain crystal structure, which illustrates how this kinase can be active. This proposal evaluates the signaling importance of ErbB3 kinase activity, and describes approaches to begin the search (and assessment) of ErbB3-specific kinase inhibitors. A. To test the hypothesis that ErbB3 kinase activity is critical for signaling in breast cancer cells and for escape from ErbB2/EGFR-targeted therapies. B. To develop in vitro assays for quantitative analysis of ErbB3 kinase activity and inhibitor assessment. C. To identify which existing kinase inhibitors inhibit ErbB3, so that they can be employed to test the principle that pharmacological ErbB3 inhibition can block ErbB signaling and growth. This Aim will also move towards identification of novel ErbB3-targeted kinase inhibitors. D. Assess the structural basis for kinase activity in ErbB3. Economic Impact: The University of Pennsylvania School of Medicine contributes substantially to the local economy. In 2008, the School created 37,000 jobs and $5.4 billion in regional economic activity, with the area's highly trained workforce producing more than 24,600 applications for just 840 open Penn staff research positions. The current proposal will create or retain 2 new jobs. PUBLIC HEALTH RELEVANCE: Successful completion of our proposed research will lead to the generation of novel ErbB3-targeted kinase inhibitors as therapeutic agents, which would have a direct and clear impact on the treatment given to patients with breast cancer that is refractory to treatment with Herceptin or Tykerb. Inclusion of ErbB3-targeted agents with Herceptin and/or Tykerb should significantly improve the response rate to these drugs in a variety of different regimens.