ABSTRACT: The epidermal growth factor receptor (EGFR) is commonly expressed in colorectal cancers but not in most normal tissues, raising the possibility that this receptor could serve as a target for highly selective therapy. Based on preclinical studies demonstrating that antagonists of EGFR resulted in the inhibition of tumor growth, the development of clinical reagents has been aggressively pursued. Early clinical studies demonstrated antitumor activity of EGFR inhibitors in patients with advanced colorectal cancer, with acceptable toxicity. This early success fueled rapid clinical development. In this article, we will review the current status of EGFR inhibitors in the treatment of patients with colorectal cancer, in an effort to describe both how far we have come as well as where we need to go in optimizing this promising therapeutic approach.
Stanley Cohen was awarded the Nobel Prize in Physiology or Medicine in 1986 for describing the epidermal growth factor (EGF) and its receptor (EGFR). In 1962, he had initially observed that injection of submaxillary gland extracts induced precocious eyelid opening and tooth eruption in newborn mice. Fifteen years later, the human homolog of the protein responsible for this activity, epidermal growth factor, and its receptor were isolated.[ 3-5] Cohen and colleagues subsequently demonstrated that this receptor had kinase activity, and that the binding and kinase activities resided in the same molecule.[6,7]
In the 1980s, studies demonstrated homology between EGFR and the proto-oncogene v-erbB, autocrine growth stimulation by TGF-alpha, and the fact that inhibition of EGFR with antibodies blocked phosphorylation, proliferation, and xenograft growth.[8-10] Also during the 1980s, several reports indicated that approximately one-third of all human epithelial cancers overexpress EGFR, and that this expression is an indicator of poor prognosis.[11-16] These findings suggested that EGFR might serve as a target for anticancer therapy.
Forty years after an unexpected laboratory observation, clinical reagents have been developed and have resulted in tumor regression in patients with colorectal and other cancers. This review will consider the compounds furthest along in clinical development against colorectal cancer, in an effort to elucidate not only how far we have come, but how far we still need to go in optimizing the use of EGFR antagonists.
Epidermal Growth Factor Receptor
EGFR (aka erbB1 or HER1) is a ubiquitous 170-kd transmembrane glycoprotein. The cell surface contains the amino-terminal glycosylated extracellular ligand-binding domain. Embedded in the cell membrane is a short, helical, hydrophobic transmembrane region, contiguous to the intracellular carboxy-terminal cytoplasmic domain that contains the tyrosine kinase domain.[17,18] Signaling by the EGFR is critical for the fetal development of epithelial, neuronal and mesenchymal tissue. Mice that lack EGFR have abnormal development of the lungs, gastrointestinal tract, skin, liver, eyes, and brain.[19-21] In the adult, EGFR signaling is tightly controlled. EGFR is a critical component of wound healing and normal cell signaling.
EGFR activation is initiated by the binding of a ligand-such as EGF, transforming growth factor (TGF)- alpha, amphiregulin, heparin-binding EGF, betacellulin, or epiregulin-to the extracellular domain. The bound receptor then homodimerizes, with phosphorylation of the tyrosine kinase domain and the subsequent cascade of signaling pathways that transmits the message to the nucleus. EGFR activates several intracellular signaling pathways including phosphatidylinositol- 3 kinase (PI3K)-Akt, Ras-Raf- MEK-MAPK, Src, PLC-gamma-1, and PAK-JNKK-JNK (Figure 1).[22,23] Successful transmission of the message results in cell division, differentiation, migration, and protection from apoptosis. The extracellular receptor is then internalized through endocytosis, with subsequent receptor degradation or recycling to the cell surface.
Rationale for EGFR as Therapeutic Target
Overexpression of EGFR has been documented in a variety of human cancers, including gliomas and carcinomas of the kidney, bladder, breast, ovary, pancreas, lung, rectum, and colon.[25-27] The EGFR is present in approximately 25% to 77% of all colorectal malignancies, depending on the method of measurement. In some studies, higher levels of EGFR expression correlate with more aggressive clinical behavior. Patients with tumors that overexpress EGFR tend to have a worse prognosis with shorter survival and increased risk of metastases.[11,12,14-16,28-33]
For example, Khorana et al recently reported a study of EGFR expression in 131 consecutive patients who underwent surgery for stage II/III primary colon cancers. Of 131 tumors, 60 (46%) had EGFR expression by immunohistochemistry (graded 1-3), while the surrounding normal colonic mucosa did not. Five-year survival in patients with no or grade 1 EGFR expression was 55%, with a median survival of 5.5 years (95% confidence interval [CI] = 4.1-8.9 years). In patients with grade 2 or 3 EGFR expression, 5-year survival was 48%, with a median survival of 4.5 years (P = .05). These data suggest that overexpression of EGFR in patients with stage II/III colorectal cancer is associated with inferior survival. Preclinical studies have also shown that cells overexpressing EGFR tend to exhibit enhanced drug and radiotherapy resistance.[35,36]
Uncontrolled EGFR activation results in uncontrolled cellular growth and may therefore be pathogenetic for some tumors. Potential causes of excessive receptor activation include mutations of the receptor or any of its domains (constitutive activation), increased ligand concentration, and decreased receptor degradation. The possibility that EGFR expression is a marker for activation that is driving some tumors led to the exploration of inhibitors of this pathway as cancer therapeutic agents. Many preclinical studies validated this hypothesis.[ 10,37-41] Given that EGFR expression is common in colorectal cancers, this setting provides a natural context in which to explore the clinical utility of the approach.
Approaches to EGFR Blockade
Several approaches to targeting EGFR are being pursued in the clinic. The furthest along in development are antibodies to the extracellular domain and small-molecular-weight tyrosine kinase inhibitors. The high target selectivity of these agents initially generated great optimism that they would provide a superior therapeutic index when compared with traditional cytotoxics and could be readily combined with other agents or modalities. In cell culture and xenograft models, antibodies and small molecules have similar effects in inhibiting the cell cycle, promoting apoptosis, and inhibiting angiogenesis.[42-49] Several distinguishing biologic features are outlined in Table 1.
In addition to EGFR antibodies and small-molecule tyrosine kinase inhibitors, other approaches to blocking EGFR activity are also in development. These include anti-EGF vaccines, immunoconjugates, multifunctional antibodies, and antisense oligonucleotides. These compounds are in early clinical trials, and will not be addressed further in this review.
Study of the EGFR pathway, including consequences of inhibition, was dramatically accelerated in the late 1970s by the identification of the A431 squamous cancer cell line, which has abundant expression of EGFR. Preclinical results obtained with A431 cells and similar lines provided the basis for the clinical development of EGFR inhibitors. The use of cell lines with extremely dense EGFR expression that are clearly dependent on this pathway for growth was critical to inhibitor development but may have contributed to an expectation that human cancers would routinely respond similarly to EGFR inhibition in vivo. As described below, this has not been the case, suggesting that EGFR expression may be necessary but not sufficient for antitumor activity.
Anti-EGFR monoclonal antibodies (eg, cetuximab [Erbitux], ABXEGF, EMD 72000) are designed to bind exclusively to the extracellular domain of EGFR.[50,51] This, in turn, inhibits the binding of ligands (such as EGF or TGF-alpha) to EGFR, and, hence, inhibits subsequent signal transduction. The receptor-antibody complex is ultimately internalized and degraded, resulting in receptor cell surface downregulation. In contrast, small-molecule inhibitors first enter the cell and then bind the receptor's tyrosine kinase domain, thereby inhibiting downstream signaling.
In cell culture and xenograft models, EGFR inhibition, regardless of method, has several consistent effects. These include (1) inhibition of angiogenesis (via downregulation of vascular endothelial growth factor)[45,52] and reduced expression of molecules associated with invasion and metastasis (eg, MMP-9, IL-8)[53,54]; (2) promotion of apoptosis[ 44,55]; (3) cell-cycle inhibition with inhibition of proliferation; and (4) potentiation of radiation and chemotherapy sensitivity.[37,38,56] This last observation in particular has guided the early clinical development of EGFR inhibitors; whereas, traditionally, single-agent activity is defined prior to combination studies, this paradigm has not been routinely employed with EGFR inhibitors (see Clinical Development section, which follows).
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