Unraveling resistance to trastuzumab (Herceptin): insulin-like growth factor-I receptor, a new suspect.

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Abstract
Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase receptor HER2 that has shown clinical activity against HER2-overexpressing breast tumors (1–4). HER2, the targeted receptor, is a member of the epidermal growth factor (EGF) receptor family of receptors, also known as the type I receptor tyrosine kinase family [for review, see (5)]. HER2 is overexpressed in 25%–30% of breast cancers, and its overexpression is associated with a high risk of relapse and death (6). In this group of tumors with unfavorable prognosis, trastuzumab has been a valuable addition to standard therapy, with the pivotal studies demonstrating a clear survival benefit (2,3). However, even in the selected group of patients with very high levels of HER2 overexpression who derive the greatest benefit from trastuzumab therapy, the response rate from this highly specific, targeted agent is limited in magnitude and duration (7).