Epidermal Growth Factor Receptor Targeting in Cancer

doi:10.1053/j.seminoncol.2006.04.003

Seminars in Oncology

Volume 33, Issue 4, August 2006, Pages 369-385

https://doi.org/10.1053/j.seminoncol.2006.04.003 Get rights and content

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family that is abnormally activated in many epithelial tumors. Several mechanisms lead to the receptor’s aberrant activation that is observed in cancer, including receptor overexpression, mutation, ligand-dependent receptor dimerization, and ligand-independent activation. Two classes of anti-EGFR agents are currently approved for the treatment of patients with cancer: cetuximab, a monoclonal antibody directed at the extracellular domain of the receptor, and gefitinib and erlotinib, oral, low-molecular-weight (MW), adenosine triphosphate (ATP)-competitive inhibitors of the receptor’s tyrosine kinase. Anti-EGFR monoclonal antibodies have demonstrated activity in the therapy of advanced colorectal carcinoma and in a variety of epithelial tumor types, including head and neck cancer and non-small cell lung cancer (NSCLC). The development of low MW, anti-EGFR tyrosine kinase inhibitors (TKIs) has been focused until recently on NSCLC, although responses have been reported for other types of cancer. Erlotinib was the only agent approved based on demonstrating improved survival, which was observed in patients with advanced NSCLC who previously had been treated with chemotherapy. Recent major advances in the EGFR field include the discovery of EGFR somatic mutations in NSCLC that have important implications for biology, treatment, clinical trial design, and methods for mutation detection. Clinical and survival benefits with anti-EGFR agents have been demonstrated in additional tumor types such as head and neck and pancreatic carcinomas. New agents with clinical activity are entering the clinic and new combinatorial approaches with anti-EGFR agents are being explored. Major efforts are, belatedly, attempting to identify molecular markers that can predict patients more likely to respond to anti-EGFR therapy.

Section snippets

Anti-EGFR Agents and Mechanisms of Action

The antibodies bind to the easily accesible extracelllular domain of the EGFR and compete with ligand binding to the receptor. For example, the murine MAb 225 and its chimeric human:murine derivative C225 (cetuximab) bind to the EGFR with high affinity (K_d = 0.39 nmol/L for cetuximab), compete with ligand binding, and block activation of receptor tyrosine kinase by the receptor ligands.15, 17, 18, 19 Recent studies have provided the structural basis for cetuximab’s mechanism of action.²⁰

Update on Clinical Activity With Monoclonal Antibodies

Anti-EGFR mAbs have shown clinical activity in a variety of solid tumors including head and neck, colon , non-small cell lung (NSCLC), and renal cell carcinomas (Table 1). The MAb most extensively studied in the clinic is cetuximab.¹⁹ The disease for which the largest amount of clinical data are reported on cetuximab treatment is colon cancer. The US Food and Drug Administration (FDA) approved cetuximab for the treatment of patients with advanced colon cancer refractory to irinotecan (CPT-11)

Low-Molecular-Weight EGFR Tyrosine Kinase Inhibitors

Early phase I studies with two oral low-MW EGFR TKIs, gefitinib and erlotonib,80, 81 were rapidly followed by extensive phase II trials exploring the use of these agents in NSCLC refractory to chemotherapy. Response rates of 10% to 18% were observed with gefitinib.82, 83 These results led to accelerated regulatory approval of gefinitib for treatment of advanced NSCLC refractory to chemotherapy in 2003. This enthusiasm, however, was followed by a reality check when a series of large phase III

Implications for the Development of Anti-receptor Agents

The clinical studies with anti-EGFR and anti-HER2 agents have demonstrated some important points that should aid in the successful development of these and other molecule-targeted agents. The first point is the usefulness of having available tumor tissue from patients participating in these trials in order to study the molecular features that may be correlated with increased sensitivity and/or resistance to these agents. A second point is that the concept of oncogene “addiction”¹¹⁶ can also

Optimal Biological Dose and Rational Biomarker Development

The reported results with gefitinib and erlotinib reviewed above will likely add fuel to the ongoing debate on how to choose the appropriate therapeutic dose level with these agents. Based on our lack of full understanding of the determinants of response, an important question is whether these agents should be initially explored at their maximally tolerated dose (MTD), or if efforts should be confined to identifying the apparent optimal biological dose (OBD). The definition of the OBD of a

Clinical Biomarker-Driven Studies With Anti-receptor Therapies

Studies identifying biomarkers of drug effects and drug sensitivity in tumors, although feasible,68, 133, 134 face the inherent difficulty of obtaining sequential tumor samples from patients only for research purposes. One approach to circumventing this difficulty involves the administration of the anti-EGFR therapy to patients with untreated, operable cancer immediately before definitive surgery. This approach has been explored in breast cancer patients treated with antiestrogens. These

Integration With Conventional Anti-cancer Therapies

One area of great interest is how to translate into human trials the synergy of anti-EGFR agents with chemotherapy or radiation that has been observed in preclinical models. An early example of concordance between preclinical and clinical data was provided with the anti-HER2 MAb trastuzumab. Our preclinical results using combined treatment with trastuzumab and doxorubicin or paclitaxel¹⁴⁵ were predictive of the improved survival observed with similar combinations in a pivotal phase III study in

Lessons for the Future

Taken together, the lack of consistent concordance in outcome between preclinical models and human trials will have implications on the way we conduct future studies with anti-EGFR agents and other new targeted therapies, either alone or in combination with conventional therapeutics. First, preclinical models may only reflect a molecular subtype of a cancer whose prevalence in that type of cancer at large is unknown and/or unpredictable. The lesson learned from the NSCLC studies is that we

Combinatorial Approaches With Other Targeted Therapies

An area of clinical research of increasing interest is the combination of either anti-EGFR or anti-HER2 agents with other therapies targeting proteins and genes. The principle behind this combinatorial approach is two-fold. First, with rare exceptions, it is unlikely that a given tumor will be dependent on just one abnormally expressed receptor or signaling pathway for its malignant behavior. Second, there is a significant level of compensatory “cross-talk” among receptors within a signaling

Conclusion

The field of targeted therapy against the EGFR and the ErbB receptor family is evolving rapidly as new insights in receptor biology as well as the results from a large number of clinical trials are becoming available. Currently, these agents have an established therapeutic role in NSCLC, colorectal cancer, head and neck cancer, and pancreatic cancer. Promising data are being accumulated in other tumor types such as renal cell carcinoma and ovarian cancer. There is a critical need for

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: Supported by a Spanish Science and Technology Ministry Grant SAF2003-03818 (J.B.), and by a Breast Cancer Research Foundation Grant (J.B.).

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Epidermal Growth Factor Receptor Targeting in Cancer

Section snippets

Anti-EGFR Agents and Mechanisms of Action

Update on Clinical Activity With Monoclonal Antibodies

Low-Molecular-Weight EGFR Tyrosine Kinase Inhibitors

Implications for the Development of Anti-receptor Agents

Optimal Biological Dose and Rational Biomarker Development

Clinical Biomarker-Driven Studies With Anti-receptor Therapies

Integration With Conventional Anti-cancer Therapies

Lessons for the Future

Combinatorial Approaches With Other Targeted Therapies

Conclusion

Mol Cell

Cancer Cell

Cancer Cell

Cell

FEBS Lett

Adv Cancer Res

J Biol Chem

Cancer Cell

J Biol Chem

J Biol Chem

J Biol Chem

Ann Oncol

Cell

Semin Oncol

Int J Radiat Oncol Biol Phys

Cancer Cell

Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer

J Clin Oncol

Untangling the ErbB signalling network

Nat Rev Mol Cell Biol

Tumor-inhibitory antibodies to HER-2/ErbB-2 may act by recruiting c-Cbl and enhancing ubiquitination of HER-2

Cancer Res

The ErbB signaling networkReceptor heterodimerization in development and cancer

EMBO J

Oncogenic kinase signalling

Nature

AKT/PKB and other D3 phosphoinositide-regulated kinasesKinase activation by phosphoinositide-dependent phosphorylation

Annu Rev Biochem

The phosphatidylinositol 3-kinase-Akt pathway in human cancer

Nat Rev Cancer

Targeting the epidermal growth factor receptor for cancer therapy

J Clin Oncol

Growth stimulation of A431 cells by EGFIdentification of high affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody

Proc Natl Acad Sci U S A

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

Cancer Res

Biological effect in vitro of monoclonal antibodies to human EGF receptors

Mol Biol Med

Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model

Clin Cancer Res

Signaling-inactive epidermal growth factor receptor/ligand complexes in intact carcinoma cells by quinazoline tyrosine kinase inhibitors

Cancer Res

Site-directed irreversible inhibitors of the erbB family tyrosine kinases as novel chemotherapeutic agents for cancer

Anticancer Drug Res

Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion

Cancer Res

Activated extracellular signal-regulated kinasesAssociation with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments

Cancer Res

ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells

Clin Cancer Res

The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells

Cancer Res

Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/Neu (erb-2)-overexpressing breast cancer cells in vitro and in vivo

Cancer Res

Reciprocal changes in p27(Kip1) and p21(Cip1) in growth inhibition mediated by blockade or overstimulation of epidermal growth factor receptors

Clin Cancer Res

Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145

Cancer Res

ZD1839, an epidermal growth factor receptor tyrosine kinase inhibitor, upregulates p27Kip1 inducing G1 arrest and enhancing the antitumor effect of interferon a

Proc Am Assoc Cancer Res

Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tysosine kinase

Cancer Res

Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin

J Clin Invest

Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma

Cancer Res

Nuclear targeting of Bax during apoptosis in human colorectal cancer cells

Oncogene