Resistance to the HER2-targeted antibody trastuzumab is a major clinical concern in the treatment of HER2-overexpressing metastatic breast cancer. Increased expression or signaling of the insulin-like growth factor-I receptor (IGF-IR) has been reported in a subset of cell lines and clinical samples derived from trastuzumab-resistant breast cancers. Genetic and pharmacologic inhibition of IGF-IR signaling has been shown to improve response to trastuzumab in trastuzumab-na？ve and trastuzumab-resistant models. In this paper, we will discuss the role of IGF-IR signaling in trastuzumab resistance. Further, we will discuss cotargeting IGF-IR and HER2 as a potential therapeutic strategy for HER2-over-expressing breast cancers that have progressed on trastuzumab treatment. 1. Introduction Trastuzumab (Herceptin; Genentech, San Francisco, CA) is a humanized monoclonal antibody against an epitope in the extracellular domain of the HER2 receptor tyrosine kinase protein [1]. HER2 is overexpressed, generally due to amplification of the her2 gene, in approximately 20–30% of human metastatic breast cancers (MBC), and is associated with reduced disease-free survival [2]. Trastuzumab effectively elicits pathologic complete responses in a large percentage of patients with HER2-positive MBC [3, 4], particularly when combined with chemotherapy [5–7]. However, some patients do not respond to trastuzumab [3–7], displaying so-called primary, de novo, or intrinsic resistance. In addition, median duration of response to trastuzumab-based therapy was reported to be less than one year in initial trials [3–7], indicating that acquired resistance is a common clinical concern. A clearer understanding of the mechanisms that contribute to trastuzumab resistance is needed in order to develop new therapeutic strategies, and, ultimately, to improve survival outcomes for patients with HER2-over-expressing breast cancer. 2. Preclinical Studies Examining IGF-IR and Trastuzumab Resistance Multiple molecular mechanisms driving trastuzumab resistance have been proposed. These mechanisms and potential treatment strategies to overcome resistance are discussed in detail in several recent and outstanding reviews [8–12]. In this paper, we will focus on one of the proposed mechanisms of trastuzumab resistance: increased signaling from the insulin-like growth factor-I receptor (IGF-IR). Lu et al. [13] first provided data to support a possible role for IGF-IR in trastuzumab resistance. The authors [13] showed that trastuzumab effectively activated a G1 arrest response in the HER2-over-expressing
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