Insulin-Like Growth Factor-I Receptor Signaling and Resistance to Trastuzumab (Herceptin)

Abstract

In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab. Thus, strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab.

The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins

“…A role for IGF-IR in patient response has been suggested by cell line studies. Lu et al (2001) reported that Herceptin resistance could occur through activation of IGF-IR. Other studies have indicated that co-targeting IGF-IR as well as ErbB2 would produce synergistic inhibition of growth in breast cancer cells (Camirand et al, 2002).…”

The GH–IGF-I axis and breast cancer

“…Similarly, it has been suggested that the IGF-1 signalling pathway also interferes with the antiproliferative actions of trastuzumab 179 .…”

“…Trastuzumab is an effective inhibitor of the growth of breast cancers overexpressing ErbB2, although not all respond and most become resistant within 12 months. This is associated with increased signalling through the IGF-I receptor 179 …”

Reversibility and recurrence of IGF-IR-induced mammary tumors

“…Also, IGF-IR is frequently overexpressed in breast cancer (Surmacz, 2000) with tyrosine kinase activity of IGF-IR increased as much as 40-fold in tumor cells compared with normal breast tissue (Resnik et al, 1998). Upregulation of IGF-IR signaling has also been implicated in mediating resistance of breast cancer cells to chemotherapeutic agents, radiation, and targeted therapies such as Tamoxifen (Parisot et al, 1999) and Herceptin (Lu et al, 2001).…”