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Cytotoxic Activity of Chimeric Toxins Containing the Epidermal Growth Factor-like Domain of Heregulins Fused to PE38KDEL, a Truncated Recombinant Form of Pseudomonas Exotoxin

Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, NIH, Bethesda, Maryland 20892

The EGF-like domains of heregulin , ß1, ß2, and ß3 were fused to a truncated form of Pseudomonas exotoxin (PE38KDEL), which contains a modified carboxyl-terminal sequence, KDEL, that increases that toxin activity. The resulting chimeric toxins were produced in Escherichia coli, purified to near homogeneity, and shown to be cytotoxic to target cells with very high activity on HTB20, N-87 MCF-7, and HepG2 cells; high activity on A431 and MDA-MB468 cells; and low activity toward SK-OV3, L929, and KB cells. The fact that cytotoxicity did not correlate with the levels of erbB2 expression indicated that another receptor in the erb family might be involved. Accordingly, cytotoxicity assays were performed on NIH/3T3 cell lines transfected with EGFR, ErbB2, ErbB3, or ErbB4. The results indicate that the heregulin toxins target ErbB4 or possibly ErbB3 but not ErbB2.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Biology, Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, NIH, 9000 Rockville Pike, 37/4E16, Bethesda, MD.

Received 3/31/94. Accepted 10/27/94.

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