Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status

Abstract

The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.

Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies

“…To better understand the influence of the EGFR blockade on radiation response in GBM, we investigated the antitumour effect of combined treatment with two mAb to EGFR and radiation in human tumour U87MG xenografts. The antitumour effect of anti-EGFR mAbs in combination with radiotherapy has been thought to result from the enhancement of the inhibition of EGFR signalling, increasing the cytotoxic effect of the radiation (Akashi et al, 2008). Consistent with these results, we found that treatment with nimotuzumab and radiation enhanced the inhibition of EGFR-signalling activation, supporting a notion that the inhibition of ERK-mediated signalling is related to radiation response in vivo in GBM (Xia et al, 1995).…”

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

“…The H292 lung cancer cell line was utilized due to its high level of EGFR and IGF-IR expression and its in vitro sensitivity to growth inhibition by anti-EGFR agents. 30,31 H292 also responds to stimulation with EGF and IGF ligands by activating EGFR and IGF-IR and downstream pathways. The increased activity of EI-Tandem compared to the monospecific Adnectins might be, in part, due to the differences in the positioning of PEG end groups in these molecules resulting from steric hinderance for binding to the EGFR or …”

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

“…Three lung cancer cell lines were selected based on the known status of EGFR (8,9), K-RAS, and TP53 (10) expression. A549 cells are known to express activated EGFR as a result of constitutive upregulation of autocrine/paracrine secretion of EGFR ligands, particularly ARG, and a resultant increase in p-EGFR.…”