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The evolution of targeted therapy of the erbB2/neu oncoprotein for human cancer therapy
The recognition that the erbB2/neu oncogene encodes a cell-surface receptor led to the development of targeted therapy. The erbB2/neu oncogene was found to encode a tyrosine kinase receptor that can form active dimers as a consequence of mutation or amplification. The receptor protein p185erbB2/neu was found to be able to dimerize with itself or with other members of the erbB family to create heteromers with active enzymatic activity and to diversify signalling and transforming patterns. When mutated or amplified, these homodimeric or heterodimeric kinases lead to human cancers, including breast and stomach malignancies. The first targeted therapeutics were monoclonal antibodies that were directed at the ectodomain of the p185erbB2/neu protein and resulted in receptor down-modulation and kinase inhibition. Unexpectedly, disabling the erbB2/neu kinase complex caused the malignant cells to convert to a more normal phenotype. The first demonstration that malignant properties could be reversed challenged all thinking at the time that malignant transformation could progressively lead to more phenotypically abnormal cells. Subsequent to phenotypical reversion, the tumour cells become sensitive to extrinsic death signals from radiation and chemotherapy. The disabling of oncoproteins that determine malignancy is an approach that is now a standard therapy for human cancer.