Abstract

Prof. Nancy Hynes, Friedrich Miescher Institute for Biomedical Research, Switzerland.



Many sub-types of the superfamily of receptor tyrosine kinases (RTKs) have been implicated in human cancer development. These transmembrane receptors can be aberrantly activated by various mechanisms including: activating point mutations, gene amplification promoting receptor overexpression and production of fusion proteins. Furthermore, coexpression of ligands and their corresponding receptors in tumor cells promotes autocrine receptor activity; while tumor-associated stromal cells can also contribute to RTK activity in a paracrine manner. I will focus on breast cancer in my presentation, a tumor type in which various RTKs have been implicated. Members of the ErbB receptor family, in particular EGFR and ErbB2 are aberrantly expressed and constitutively active in primary breast tumors. ErbB receptors have been successfully inhibited using either ectodomain binding antibodies or small molecular tyrosine kinase inhibitors (TKIs) that compete with ATP for receptor binding, thereby blocking activity. I will discuss the mechanisms that are likely to contribute to clinical efficacy and pathways that may contribute to resistance (1). Since ErbB receptors are aberrantly expressed in 20-25% of breast tumors, there is a need for uncovering other RTKs that might also be successfully targeted in this tumor type. With this in mind, we have recently shown that the Ret receptor is expressed in primary breast tumors. Ret is a well characterized oncoprotein in thyroid cancer, where it is constitutively activated by various mutations and acts independently of a ligand (GDNF family members) or its coreceptor (GFR alpha family members). In breast cancer, the Ret receptor is WT but many tumors co-express GDNF and GFR alpha1. Using breast cancer cell lines, we have shown that Ret is activated in response to GDNF and ligand-treated cells show enhanced transforming properties (anchorage independent proliferation and migration) (2). Future experiments are aimed at studying the effects of Ret blockade on in vivo tumor growth. Finally, genetic evidence of various types has implicated aberrant FGFR activation in human breast cancer. We have been exploring the potential of targeting the FGFR family using FGFR selective TKIs (3). New results showing that impact of FGFR blockade on primary tumor growth and metastasis formation will be presented.

(1) N.E.Hynes, H.A.Lane (2005) ErbB receptors and cancer: the complexity of targeted inhibitors. Nature Rev Cancer 5: 341-354. (2) A. Boulay, M. Breuleux, C. Stephan, C. Fux, C. Brisken, M. Fiche, M. Wartmann, M. Stumm, H.A. Lane, N.E.Hynes (2008) The Ret receptor tyrosine kinase functionally interacts with ER alpha signaling pathway in breast cancers. Cancer Research 68: 3743-3751. (3) M. Koziczak, T.Holbro, N.E.Hynes (2004) Blocking FGFR signaling inhibits breast cancer cell proliferation through down-regulation of D type cyclins. Oncogene, 23: 3501-3508 .

Host: Prof Jean-Paul Thiery