Deciphering the role of insulin-like growth factor-I receptor in trastuzumab resistance

Abstract

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-naïve 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.

Figure 1

IGF-IR blockade reduces phosphorylation of HER2 in trastuzumab-resistant cells. SKBR3 cells with acquired resistance to trastuzumab were untreated or treated with 0.25 μg/mL alpha IR3 IGF-IR monoclonal antibody overnight. Total protein lysates were western blotted for phosphorylated and total HER2 and IGF-IR. Actin served as a loading control.

Figure 2

IGF-IR signaling pathway. Increased expression of IGF-IR, or IGF-IR interaction and crosstalk with HER2 have been reported in models of Herceptin resistance. PI3K signaling has been implicated as a potential mechanism of IGF-IR-mediated Herceptin resistance. Inhibition of IGF-IR has been shown to increase sensitivity to Herceptin in preclinical studies.