EGFR-targeting drugs in combination with cytotoxic agents: from bench to bedside, a contrasted reality

Abstract

The clinical experience recently reported with epidermal growth factor receptor (EGFR)-targeting drugs confirms the synergistic interactions observed between these compounds and conventional cytotoxic agents, which were previously established at the preclinical stage. There are, however, examples of major gaps between the bench and the bedside. Particularly demonstrative is the failure of the tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) combined with chemotherapy in pretreated nonsmall cell lung cancer patients. These discrepancies can be due to several factors such as the methodology used to evaluate TKI plus cytotoxic agent combinations in preclinical models and the insufficient consideration given to the importance of the drug sequences for the tested combinations. Recent advances in understanding the biologic basis of acquired resistance to these agents have great potential to improve their clinical effectiveness. The purpose of this review is to critically examine the experimental conditions of the preclinical background for anti-EGFR drug -cytotoxic agent combinations and to attempt to explain the gap between clinical observations and preclinical data. The epidermal growth factor receptor (EGFR) is present in many cell types and can be considered as one of the best-characterised ligand-receptor systems (Mendelsohn and Baselga, 2006). Epidermal growth factor receptor is a 170-kDa cell surface glycoprotein containing three well-identified domains: an extracellular ligandbinding domain, a hydrophobic membrane-spanning domain and a cytoplasmic portion containing the tyrosine kinase activity. The hyperactivation of EGFR signalling in tumours occurs via independent or combined mechanisms: overexpression of the receptor itself, autocrine overproduction of ligand with mainly EGF and tumour growth factor (TGFa), and EGFR mutations, notably through the variant III that maintains the EGFR signalling pathway in a state of continuous activation. Binding of a growth factor to its receptor initiates organised and oriented biochemical intracellular events. These include the activation of the receptor, a cascade of phosphorylation with different protein kinases and, at the nuclear level, the activation of transcription factors. The effects of EGFR activation on tumour cells are multiple and convergent, thus favouring uncontrolled cell growth with an increase in cell mobility and cell proliferation, a decrease in apoptotic machinery and stimulation of angiogenesis. In the clinic, EGFR overexpression has been associated with chemoresistance, disease progression and poor survival (Baselga, 2002). Considering the set of therapeutic tools targeting EGFR (Castillo et al, 2004), there are two well-identified categories of drugs, with monoclonal antibodies (mAbs) on one hand and tyrosine kinase inhibitors (TKIs) on the other. Both treatment tools have reached a mature stage of clinical development. Current therapeutic applications with anti-EGFR drugs show encouraging clinical results. This is true mainly for combin...

Incidence and risk of hypomagnesemia in advanced cancer patients treated with cetuximab: A meta-analysis

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Epigallocatechin gallate sensitizes CAL-27 human oral squamous cell carcinoma cells to the anti-metastatic effects of gefitinib (Iressa) via synergistic suppression of epidermal growth factor receptor and matrix metalloproteinase-2

“…Gefitinib (Iressa), an EGFR inhibitor, has shown obvious in vitro and in vivo anticancer activity through reduced EGFR expression in cancer cell lines, including prostate, breast, ovarian, colon and HNSCC (25,26). Preclinical therapy evidence suggests that gefitinib may enhance anticancer activity compared to a variety of cytotoxic drugs including platinum derivatives, taxanes, doxorubicin or topotecan (27). Gefitinib was found to competitively inhibit the autophosphorylation of the catalytic domain of the EGFR (19,20).…”

Antibodies specifically targeting a locally misfolded region of tumor associated EGFR

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