This is a competitive renewal for a project that has been directed at understanding the role of aberrant TGFalpha signaling as a basis for disrupted growth regulation in colon cancer. We have found that TGFalpha is constitutively upregulated in highly malignant colon cancer cells, but is downregulated in Go premalignant and normal cells. This constitutive TGFalpha expression leads to a low, but constitutive activation of the EGFR, ErbB2 and downstream signaling including the PLCgamma, MAPK and PI3K pathways. These pathways generate growth factor independence as reflected by lack of exogenous growth factors for cell cycle re-entry and constitutive cell survival signaling. Colon cancer is one of the histological types of cancer showing a low rate of response to EGFR antagonism in the clinic as several small molecular weight tyrphostin derivatives as well as monoclonal antibodies are in various stages of development. The small molecular weight EGFR antagonists appear to be pan ErbB antagonists as well, but we have found that they fail to inhibit autophosphorylation of Y1248 by activated ErbB2 kinase in EGFR/ErbB2 heteromers. This is important because ErbB2 kinase, EGFR kinase independent signaling is prevalent in colon cancer cells and can lead to the activation of the PI3K or PLCgamma pathways and cell survival signaling. Thus, we have identified novel mechanisms of ErbB2 mediated signal diversification arising from aberrant autocrine TGFalpha which can circumvent the effects of this class of compounds in the clinic. Consequently, it is important to understand this signal diversification in colon cancer in order to optimize combination therapy with EGFR and ErbB2 antagonists.
Specific Aims for the next cycle of the project are: 1. Determine the role of ErbB2 in the specification of essential signaling contributing to the malignant phenotype in colon cancer cells. 2. Determine how repression of ErbB2 dependent kinase signaling affects therapy by EGFR antagonists. 3. Determine mediators of cell survival signaling by ErbB family autocrine activation in colon carcinoma cells.
