Cellular responses to EGFR inhibitors and their relevance to cancer therapy

doi:10.1016/j.canlet.2007.02.006

Cancer Letters

Volume 254, Issue 2, 8 September 2007, Pages 165-177

https://doi.org/10.1016/j.canlet.2007.02.006 Get rights and content

Abstract

EGFR is a trans-membrane receptor tyrosine kinase that belongs to the HER family of receptors. The EGFR family plays an essential role in normal organ development by mediating morphogenesis and differentiation. Unlike normal cells that have tight regulatory mechanisms controlling EGFR pathways, tumor cells often have dysregulated EGFR signaling through receptor overexpression and/or mutation. This leads to proliferation under adverse conditions, invasion of surrounding tissues, and increased angiogenesis as well as resistance to radiation and chemotherapy. Therefore, EGFR is a legitimate therapeutic target. Numerous EGFR inhibitors are under development, but to date only four of them are FDA-approved, including two that inhibit the receptor’s intracellular tyrosine kinase activity (gefitinib and erlotinib) and two that block extracellular ligand binding (cetuximab, and most recently panitumumab). In this review, we focus on how these different inhibitors affect EGFR signaling and the mechanisms by which they potentiate the effects of chemotherapy and radiation therapy. Numerous clinical trials have been conducted with these agents either as monotherapy, in combination with chemotherapy, or concurrently with radiation. Unfortunately, many of the clinical trials reported so far have shown at best limited gains; therefore, understanding the actions of these agents is essential to improving their efficacy in the treatment of cancers.

Introduction

Despite significant advances in systemic therapies, radiation oncology, and surgical techniques, many patients with cancer are still incurable. A novel therapeutic approach has been to target the epidermal growth factor receptor (EGFR), which is often mutated and/or overexpressed in many tumors and regulates proliferation, apoptosis, angiogenesis, tumor invasiveness, and distant metastases [1], [2]. Specifically, inhibition of the EGFR signaling pathways has been accomplished extracellularly with specific antibodies to block ligand binding or intracellularly with small molecule inhibitors. This review will focus on the cellular responses to these EGFR inhibitors and their implications for cancer therapy.

Section snippets

EGFR signaling

EGFR is a trans-membrane receptor tyrosine kinase that belongs to the HER family of receptors [3]. To date four member of this family have been identified including EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3) and HER4 (erbB-4). A wide variety of cancers express EGFR (Table 1). The N-terminus extracellular portion of EGFR can bind a variety of ligands. Based on their affinities for various receptors, these ligands are divided into three different groups. Epidermal growth factor (EGF),

Classes of EGFR inhibitors

Numerous strategies have been explored to target EGFR to inhibit tumor growth including monoclonal antibodies (MoAbs; e.g. cetuximab, panitumumab), small molecule tyrosine kinase inhibitors (TKIs; e.g. gefitinib, erlotinib), ligand-linked toxins, and antisense oligonucleotides. MoAbs block ligand from binding to the extracellular domain of the receptor whereas TKIs target the ATP-binding pocket of the cytoplasmic domain to inhibit receptor phosphorylation. To date, the FDA has approved only two

Receptor mutations and response to inhibitors

Mutations in genes encoding for EGFR or its signaling molecules are observed in many tumors. Glioblastomas often express a mutant variant of EGFR, known as EGFRvIII, which constitutively activates PI3K and confers enhanced tumorigenicity [14]. Mellinghoff et al. studied patients with glioblastomas who had been treated with EGFR kinase inhibitors [35]. Their study demonstrated that patients with co-expression of EGFRvIII and PTEN were more likely to show a radiologic response to an EGFR

Anti-proliferative effects

EGFR inhibition has significant effects on cellular proliferation. Huang et al. showed that micromolar concentrations of gefitinib inhibited cell proliferation in a dose-dependent manner in SCCHN cell lines [39]. Even cell lines with relatively low levels of EGFR expression showed modest levels of inhibition. Flow cytometric analysis demonstrated that gefitinib treatment led to an accumulation of cells in the G₁ phase with a simultaneous decrease in cell numbers in S phase. This G₁ phase arrest

Effects on migration and invasion

EGFR activation results in PLC-γ phosphorylation and subsequent hydrolysis of phosphatidylinositol 4,5 biphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) (see Fig. 1). This in turns leads to the release of gelsolin and other actin-binding proteins that can modify the actin cytoskeleton [41], [42]. Hydrolysis of PIP2 occurs preferentially at the leading edge of a cell, which provides asymmetry in intracellular signaling and leads to the formation of lamellopodia

Anti-angiogenic response

Decreased expression of vascular endothelial growth factor (VEGF), a key angiogenic factor, may account for some of the inhibition of tumor growth by EGFR blockade in vivo. EGF induces VEGF expression in many cell lines [51], [52]. Conversely, our own data and that of many other groups indicate that pharmacological inhibition of EGFR can decrease VEGF expression and consequently angiogenesis in many tumor types [31], [39], [53], [54], [55], [56], [57], [58]. Particularly interesting is a study

Radiosensitization

Growth factors have been shown to mediate cellular responses to radiation in numerous tissues. Some studies have shown that EGF treatment leads to radiosensitization [63], [64], [65]. However, in retrospect, it is very possible that radiosensitization with EGF in these studies occurred because prolonged exposure to EGF resulted in degradation of EGFR. In fact, most studies have shown the opposite, that activating the EGFR pathway leads to decreased sensitivity to radiation. For example,

Chemosensitization

EGF treatment of cells has been shown to be associated with resistance to chemotherapeutic agents including doxorubicin and topoisomerase II inhibitors [90], [91]. Fan et al. found significant tumor regression of A431 squamous cell carcinoma xenografts in nude mice treated with C225 in combination with cisplatin whereas either agent by itself had no effect [92]. Likewise, studies with doxorubicin in combination with anti-EGFR monoclonal antibodies demonstrated marked tumor regression of A431

Clinical trials: radiotherapy and EGFR inhibition

The addition of cetuximab to radiotherapy in SCCHN has led to improved overall survival and locoregional control in a clinical phase III trial. Bonner et al. randomized 424 patients with locally advanced SCCHN to radiotherapy plus weekly cetuximab or radiotherapy alone [101]. After a median follow-up of 54 months, overall survival was 55% months at three years in the combined therapy arm versus 45% in the radiation alone arm (median 49 months versus 29 months), a difference that reached

Gefitinib and non-small cell lung cancer

While some tumors clearly exhibit dramatic shrinkage in response to EGFR inhibitors [11], [12], clinical phase III randomized trials have not shown a survival advantage with gefitinib. In the phase III ISEL trial for locally advanced or metastatic NSCLC, gefitinib monotherapy failed to demonstrate a survival benefit in patients who had received one or two prior chemotherapy regimens [102]. Likewise, in the SWOG0023 trial for patients with Stage III NSCLC, gefitinib monotherapy did not improve

Conclusions

There is a wealth of preclinical data indicating why EGFR inhibitors should be effective in controlling cancers. These agents could block cancer growth via inhibition of tumor proliferation, apoptosis, angiogenesis, migration, invasion, and metastases. However, clinical trials in patients with cancer have shown only modest gains with these inhibitors, particularly when they have been given as monotherapy. There appears to be greater promise when these agents are combined with radiation or

Acknowledgement

The preparation of this manuscript was in part supported by NIH R01 CA093638.

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Mini-reviewCellular responses to EGFR inhibitors and their relevance to cancer therapy

Abstract

Introduction

Section snippets

EGFR signaling

Classes of EGFR inhibitors

Receptor mutations and response to inhibitors

Anti-proliferative effects

Effects on migration and invasion

Anti-angiogenic response

Radiosensitization

Chemosensitization

Clinical trials: radiotherapy and EGFR inhibition

Gefitinib and non-small cell lung cancer

Conclusions

Acknowledgement

Pharmacol. Ther.

J. Biol. Chem.

J. Biol. Chem.

Crit. Rev. Oncol. Hematol.

Curr. Top. Dev. Biol.

Curr. Top. Dev. Biol.

Gene

Cancer Cell

J. Biol. Chem.

FEBS Lett.

Crit. Rev. Oncol. Hematol.

Pharmacol. Ther.

Exp. Cell Res.

Cell

Biochem. Biophys. Res. Commun.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

J. Biol. Chem.

J. Biol. Chem.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Biochem. Pharmacol.

Biochem. Pharmacol.

Why the epidermal growth factor receptor? The rationale for cancer therapy

Oncologist

The EGFR family and its ligands in human cancer. Signalling mechanisms and therapeutic opportunities

Eur. J. Cancer

Protein modules and signalling networks

Nature

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

N. Engl. J. Med.

EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy

Science

Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification

Oncogene

A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity

Proc. Natl. Acad. Sci.

Structural alterations of the epidermal growth factor receptor gene in human gliomas

Proc. Natl. Acad. Sci.

Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer

Cancer Res.

The EGF receptor: a nexus for trafficking and signaling

Bioessays

Regulation of the Ras signalling network

Bioessays

The phosphatidylinositol 3-kinase Akt pathway in human cancer

Nat. Rev. Cancer

New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/akt pathway

Proc. Natl. Acad. Sci.

Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting

EMBO J.

STAT proteins: novel molecular targets for cancer drug discovery

Oncogene

Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors

Mol. Biol. Med.

Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies

Cancer Res.

ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy

Cancer Res.

Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor

Clin. Cancer Res.

Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase

Clin. Cancer Res.

Mini-review
Cellular responses to EGFR inhibitors and their relevance to cancer therapy