Trastuzumab is the first Food and Drug Administration (FDA)-approved therapeutic targeting a HER-family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment of HER2-positive breast cancer, a substantial proportion of patients will not respond to trastuzumab-based regimens (primary resistance), and those who do respond will often lose clinical benefits (i.e., secondary resistance). Although multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which together demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including the sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of resistance as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance.
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