Aberrant expression of the epidermal growth factor receptor (EGFR) system has been reported in a wide range of epithelial cancers. In some studies, this has also been associated with a poor prognosis and resistance to the conventional forms of therapies. These discoveries have led to the strategic development of several kinds of EGFR inhibitors, five of which have gained US Food and Drug Administration approval for the treatment of patients with non-small-cell lung cancer (gefitinib and erlotinib), metastatic colorectal cancer (cetuximab and panitumumab), head and neck (cetuximab), pancreatic cancer (erlotinib) and breast (lapatinib) cancer. Despite these advances and recent studies on the predictive value of activating EGFR mutation and KRAS mutations with response in non-small-cell lung cancer and colon cancer patients, there is currently no reliable predictive marker for response to therapy with the anti-EGFR monoclonal antibodies cetuximab and panitumumab or the small molecule EGFR tyrosine kinase inhibitors gefitinib and erlotinib. In particular, there has been no clear association between the expression of EGFR, determined by the US Food and Drug Administration-approved EGFR PharmDX kit, and response to the EGFR inhibitors. Here, we discuss some of the controversial data and explanatory factors as well as future studies for the establishment of more reliable markers for response to therapy with EGFR inhibitors. Such investigations should lead to the selection of a more specific subpopulation of cancer patients who benefit from therapy with EGFR inhibitors, but equally to spare those who will receive no benefit or a detrimental effect from such biological agents.
Background:The combination of the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib with gemcitabine obtained FDA approval for treating patients with pancreatic cancer. However, duration of response is often limited and there is currently no reliable predictive marker.Methods:We determined the sensitivity of a panel of human pancreatic tumour cell lines to treatment with afatinib, erlotinib, monoclonal antibody (mAb) ICR62, and gemcitabine, using the Sulforhodamine B colorimetric assay. The effect of these agents on cell signalling and cell-cycle distribution was determined by western blot and flow cytometry, respectively.Results:At 200 n, ICR62 had no effect on growth of these tumour cells with the exception of BxPC-3 cells. BxPC-3 cells were also sensitive to treatment with afatinib and erlotinib with respective IC50 values of 11 and 1200 n. Compared with erlotinib, afatinib was also more effective in inhibiting the growth of the other human pancreatic tumour cell lines and in blocking the EGF-induced phosphorylation of tyrosine, EGFR, MAPK, and AKT. When tested in BxPC-3 xenografts, afatinib induced significant delay in tumour growth.Conclusion:The superiority of afatinib in this study encourages further investigation on the therapeutic potential of afatinib as a single agent or in combination with gemcitabine in pancreatic cancer.
Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto-and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR-or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules.
(Santon et al., 1986;Ozanne et al., 1986;Velu et al., 1987; Difore et al., 1987;Harris et al., 1990). In addition, some of these tumours produce ligands for the receptor and it has been suggested that an autocrine mechanism is involved in progression of cancers of this type (Sporn & Roberts 1985;Imanishi et al., 1988;Nistar et al., 1988; Dernyck 1990;Tateishi et al., 1990;Yoshida et al., 1990; Morishige et al., 1991). Over-expression of the EGFR by tumour cells, compared to their normal counterparts, has been reported for a number of squamous cell carcinomas (e.g. Cowley et Hendler et al., 1984;Sainsbury et al., 1985;Gullick et al., 1986) and this in turn was also correlated to poor prognosis in patients with some of these carcinomas (reviewed by Gullick, 1991 We have reported (Modjtahedi, et al., 1992) the preparation and properties of ten rat mAbs that bind to three distinct epitopes (A,B,C) on the external domain of the EGFR using as immunogen the human squamous cell carcinoma HN5. While all of the mAbs against epitopes B and C blocked the binding of EGF and TGFa to the receptor on a number of squamous carcinoma cell lines the antibodies against epitope C were an order of magnitude better than the others at inhibiting cell growth. The best antibody, ICR16, inhibited completely the growth of HN5 cells in vitro at antibody concentrations above 1 nM. However, none of the antibodies was of the IgG2b isotype and therefore would not be expected to interact efficiently with the host immune effector functions in rat, mouse or man. Since our intention is to test the effectiveness of antibodies in the clinic we report here the preparation of a second series of antibodies using as immunogen the EGFR over-expressing breast carcinoma (Filmus et al., 1985) searching particularly for IgG2b antibodies with growth inhibitory properties. Materials and methods Cell lines
Numerous reports have shown an association between overexpression of the epidermal growth factor receptor (EGFR), and poor prognosis in head and neck squamous cell carcinomas (HNSCC), however, the underlying mechanisms are still unclear. In the present study, we set out to determine whether EGFR expression was associated with in vitro invasive capacity in a panel of four established and ten newly derived HNSCC lines. Ten of the cell lines expressed high levels of EGFR as determined by a ligand‐binding assay and dot blot analysis, whereas the remaining four showed weak overexpression or normal levels of EGFR. The ability of cells to invade through Matrigel was found to be higher in the EGFR overexpressing cell lines (p < 0.0001). Expression levels of matrix metalloproteinases (MMP‐1, MMP‐2, MMP‐3, MMP‐7, MMP‐9, MMP‐10, MMP‐11, MMP‐13, MT1‐MMP) and tissue inhibitors of MMP (TIMP‐1, TIMP‐2) were evaluated by semiquantitative RT‐PCR, substrate zymography and western blot. We found a strong positive correlation between EGFR levels and the expression of MMP‐9 mRNA (r2 = 0.95; p < 0.0001), MMP‐9 enzyme activity (r2 = 0.8099; p < 0.0001) and an inverse correlation with TIMP‐1 (r2 = 0.48; p = 0.0059). In six selected HNSCC lines, in vitro invasion was assayed in the presence of an anti‐EGFR monoclonal antibody, ICR62. A significant reduction of invasion in four selected EGFR‐overexpressing cell lines was found with 30 nM ICR62 (from 50% to 70%; p < 0.001) but there was no effect in two cell lines with normal EGFR levels. Our results show that the in vitro invasive phenotype of HNSCC lines correlates with high EGFR and MMP‐9 expression, and it is therefore suggested that the EGFR signaling pathway might play an important role in the invasive behavior of HNSCC via specific upregulation of MMP‐9 and downregulation of TIMP‐1. Int. J. Cancer 86:307–317, 2000. © 2000 Wiley‐Liss, Inc.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.