However, despite these advances, many patients simply do not resp

However, despite these advances, many patients simply do not respond to or acquire selleck Bosutinib resistance to therapy with the HER inhibitors [8]. The Insulin-like Growth Factor receptor (IGF-IR) is another very well characterized RTK and the main mediator of the biological action of IGF-I and IGF-II [13,14]. The IGF signalling network includes the IGF-I and IGF-II ligands, insulin, the cell surface receptors IGF-IR, IGF-IIR and the Insulin receptor (IR) as well as a group of regulatory IGF binding proteins (IGFBPs) [14-16]. The IGF-IR signalling axis is implicated in the regulation of a number of cellular processes including cell growth, survival and cell differentiation, and its aberrant activation has been associated with increased cell proliferation, reduced apoptosis, transformation, angiogenesis and increased cell motility and resistance to chemotherapy and radiotherapy in several types of human cancers [14,17,18].

As a result, the IGF-IR network has emerged as an attractive target for the development of new therapeutic strategies and a number of small molecule IGF-IR TKIs and anti-IGF-IR mAbs have been developed which are at different stages of preclinical evaluations and clinical trials in several types of human malignancies. In addition, recent studies have demonstrated that IGF-IR is implicated in resistance to anti-HER targeted therapy and consequently, simultaneous targeting of HER family members and IGF-IR may lead to a superior therapeutic effect in cancer patients.

We have recently reported the superiority of afatinib, an irreversible erbB family blocker, compared to the anti HER monoclonal antibody (mAb) ICR62 and first generation TKI erlotinib in inhibiting the growth of a panel of human pancreatic tumour cells [19]. The aim of this study was to investigate the sensitivity of the same panel of pancreatic cancer cell lines to Brefeldin_A treatment with an IGF-IR TKI, NVP-AEW541 [20], when used alone or in combination with afatinib, anti-EGFR mAb ICR62 or gemcitabine. In addition, we investigated the effect of these inhibitors on the phosphorylation of HER receptors, IGF-IR and downstream molecules such as MAPK and AKT and whether there was any association between the expression of the receptor and sensitivity to treatment.

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