Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells

Abstract

De novo and acquired resistance to the anti-tumour drug gefitinib (ZD1839; Iressa), a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) has been reported. We have determined whether signalling through the IGF-I receptor (IGF-1R) pathway plays a role in the gefitinib-acquired resistance phenotype. Continuous exposure of EGFR-positive MCF-7-derived tamoxifen resistant breast cancer cells (TAM-R) to 1 mM gefitinib resulted in a sustained growth inhibition (90%) for 4 months before the surviving cells resumed proliferation. A stable gefitinibresistant subline (TAM/TKI-R) was established after a further 2 months and this showed no detectable basal phosphorylated EGFR activity. Compared with the parental TAM-R cells, the TAM/ TKI-R cells demonstrated (a) elevated levels of activated IGF-1R, AKT and protein kinase C (PKC)d, (b) an increased sensitivity to growth inhibition by the IGF-1R TKI AG1024 and (c) an increased migratory capacity that was reduced by AG1024 treatment. Similarly, the EGFR-positive androgen-independent human prostate cancer cell line DU145 was also continuously challenged with 1 mM gefitinib and, although substantial growth inhibition (60%) was seen initially, a gefitinibresistant variant (DU145/TKI-R) developed after 3 months. Like their breast cancer counterparts, the DU145/TKI-R cells showed increases in the levels of components of the IGF-1R signalling pathway and an elevated sensitivity to growth inhibition by AG1024 compared with the parent DU145 cell line. Additionally, DU145/TKI-R cell migration was also decreased by this inhibitor. We have therefore concluded that in breast and prostate cancer cells acquired resistance to gefitinib is associated with increased signalling via the IGF-1R pathway, which also plays a role in the invasive capacity of the gefitinib-resistant phenotype.

The insulin-like growth factor-1 receptor inhibitor PPP produces only very limited resistance in tumor cells exposed to long-term selection

“…However, a very important and general drawback with cancer drugs, also concerning targeting with small molecules and antibodies (Chen et al, 2004;Jones et al, 2004;Nagata et al, 2004;Peggs, 2004), is the generation of drug resistance (Longley and Johnston, 2005). For this reason, we found it highly relevant to investigate whether resistance to PPP may occur after long-term treatment in a cellular context, as well as to characterize the obtained resistance.…”

A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity

“…[14][15][16] The interplay of these two receptor pathways may lead to resistance by the tumor to inhibition of one receptor via compensatory upregulation/activation of the reciprocal receptor, and dual inhibition of EGFR and IGF-1R has been shown to improve anti-tumor activity and overcome resistance to therapy against a single receptor in preclinical models. [17][18][19][20][21][22][23][24] Moreover, co-expression of EGFR and IGF-1R has been reported in many human tumors, including lung, colorectal and pancreatic carcinoma, [25][26][27] supporting dual targeting of these two receptors in these indications. Clinically, EGFR inhibitors are known to be efficacious in only a subpopulation of cancer patients, and intense research for molecular predictors of clinical outcomes to EGFR targeted therapies has identified K-Ras mutation as a predictive biomarker of resistance to EGFR mAbs treatment in colorectal cancer and EGFR gene mutation or high copy number as strong indicators of response to EGFR TKIs in lung cancer.…”

Superior Antitumor Activity of a Novel Bispecific Antibody Cotargeting Human Epidermal Growth Factor Receptor 2 and Type I Insulin-like Growth Factor Receptor

“…This activates the kinase activity of IGF-IR, and triggers downstream signaling via the PI3K/Akt and Ras/MAPK pathways, resulting in increased cell survival and cell proliferation (16,17). Elevated IGF-IR is found in many tumor malignancies, including breast, prostate, and lung cancers (18,19). In addition, overexpression of IGF-IR has been associated with disease progression and cancer metastasis (20,21).…”