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Inactivation of EGFR family members (EGFRs) represents a promising strategy for the development of selective therapies against epithelial cancers. Current therapies such as cetuximab (Erbitux), gefitinib (Iressa) or trastuzumab (Herceptin) target EGFR or HER-2 but not both. Since solid tumors express different EGFRs, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. We have identified a natural inhibitor of EGFRs called ERRP (EGFR-Related Protein), a 53- 55 kDa protein, which is present in most, if not all, normal human epithelial cells. The growth of colon (HCT-116, Caco-2 and HT-29), lung (NCI-H226 and NCI-H522) and breast (MDA-MB-468 and SKBR-3) cancer cell lines expressing varying levels of EGFR, HER-2, and/or HER-4 was inhibited by recombinant ERRP in a dose-dependent manner. In contrast, ERRP caused no inhibition in the growth of normal mouse fibroblast cell lines, and the growth of the non-transformed rat small intestinal IEC-6 cells expressing relatively low levels of EGFRs was inhibited only at high doses of ERRP. Ligand-induced activation of both EGFR and HER-2 was inhibited by ERRP in colon, lung and breast cancer cells expressing high levels of EGFR or HER-2. In contrast, cetuximab inhibited the growth and ligand-induced activation of EGFR in cell lines expressing high levels of EGFR, while trastuzumab was effective only in HER-2 overexpressing cells. Furthermore, ERRP, but not cetuximab or tratsuzumab, significantly induced apoptosis of colon, lung and breast cancer cells. Our results suggest that ERRP is an effective pan-erbB inhibitor and thus may be a potential therapeutic agent for a wide variety of epithelial cancers expressing different levels and subclass of EGFRs.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]