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Anti-EGFR Mechanism of Action: Antitumor Effect and Underlying Cause of Adverse Events

Anti-EGFR Mechanism of Action: Antitumor Effect and Underlying Cause of Adverse Events

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers. Two main classes of anticancer agents affect the EGFR: those targeting the extracellular ligand-binding domain and those that block the intracellular tyrosine kinase (TK) domain. Cetuximab (Erbitux) is a mouse/human chimeric monoclonal antibody that targets the ligand-binding domain of the EGFR, whereas erlotinib (Tarceva) and gefitinib (Iressa) are small-molecule TK inhibitors. Common toxicities of agents targeting the EGFR differ from those associated with traditional chemotherapy. Given the common pathway through which these agents work, some adverse events are similar. Many patients treated with these agents develop an acne-like rash on the face and upper body, most likely related to keratinocyte alterations and hair follicle proliferation and maturation. Although clinical manifestation of this reaction closely resembles acne vulgaris, the histology is more similar to infectious folliculitis. Other adverse events appear to be related to a drug class or individual agent. For example, interstitial lung disease is a rare but potentially fatal reaction that has been reported with gefitinib. Hypomagnesemia reported in association with cetuximab may be related to EGFR blockade in the kidney. Anaphylactic or anaphylactoid infusion reactions are also seen with cetuximab, as with other monoclonal antibodies.

The epidermal growth factor receptor (EGFR) is among the most widely studied growth factor receptors due to its ubiquity and pleiotropic signaling effects.[1,2] EGFR is expressed by nearly all adult human tissues, with the notable exception of hematopoietic cells.[2,3] Activation of EGFR results in a range of effects, including cell proliferation, differentiation, migration, adhesion, and inhibition of apoptosis.[4] It also enhances processes crucial to tumor growth and progression, such as angiogenesis, tumor invasiveness, and metastatic spread.[5] EGFR is overexpressed by many human cancers, while its signaling is upregulated due to autocrine stimulation in others.[1,5] Its expression has been shown to correlate with disease progression, reduced survival, poor response to treatment, and chemotherapy resistance in several human cancers.[5]

For these reasons, EGFR is a rational target for the design and development of novel agents that aim to distinguish malignant and nonmalignant cells. Two main categories of compounds have been developed: agents that target the extracellular domain of the receptor and those that target the intracellular tyrosine kinase (TK) domain (Table 1). Both approaches result in blockade of signal transduction, thereby preventing the downstream effects normally associated with EGFR activation.[4,5]

The monoclonal antibody cetuximab (Erbitux) is the first commercially available agent designed to target the EGFR extracellular domain; it is approved for use in patients with EGFR-expressing, metastatic colorectal cancer.[6] Gefitinib (Iressa) and erlotinib (Tarceva) are small-molecule inhibitors of the TK domain, each initially approved for use in patients with advanced non-small-cell lung cancer who have progressed on at least one (erlotinib) or two (gefitinib) prior chemotherapy regimens.[7,8] (As of June 2005, the US Food and Drug Administration has limited the commercial use of gefitinib to those patients currently receiving and benefiting from the drug or those who have received it and benefited from it in the past, pending the outcomes of additional studies.[9])

Despite the differences in chemical structure and mechanism of action of these two drug classes, many of the resultant side effects are similar due to their effects on a common target. This article further describes the EGFR and adverse event profiles of the agents that target it, with the goal of distinguishing adverse events related to EGFR inhibition from those unique to the individual drugs.

The Epidermal Growth Factor Receptor

Structure and Activation

The EGFR, also known as HER1 or ErbB1, is a 170-kD glycoprotein that consists of an extracellular ligand-binding domain, a hydrophobic transmembrane region, and an intracellular TK domain. Ligands for the EGFR include EGF, transforming growth factor-alpha (TGF-α), amphiregulin, heparin-binding EGF, betacellulin, and epiregulin.[4] EGFR exists as a monomer in the cell membrane. Upon ligand binding, individual receptors cluster on the cell surface, which facilitates dimerization.[10] EGFR can form a homodimer with another EGFR monomer or a heterodimer with another member of the erbB family (eg, HER2/neu, HER3, or HER4).[4,11] Dimerization is followed by TK activation and autophosphorylation on tyrosine residues, key steps to the initiation of downstream physiologic and pathogenic events (Figure 1). Ultimately signaling is “turned off” by internalization of receptor/ligand complexes.[4,5,12]

The precise signaling pathways that are activated in response to EGFR-ligand binding depend on both the activating ligand and coreceptor to which EGFR dimerizes.[4,13] Major pathways include the MAPK and PI-3K/Akt pathways.[5,11] The Ras-Raf-MEK-MAPK pathway produces cell proliferation and angiogenesis, inhibits apoptosis, and increases metastatic spread. The PI-3K/Akt pathway affects cell survival, metabolism, and proliferation, and it inhibits apoptosis.[11]

Physiologic Role of EGFR Signaling

Signaling by EGFR is critical for epithelial development, proliferation, and organogenesis.[4] Studies with EGFR knockout mice demonstrate that the lack of EGFR results in embryonic and perinatal mortality. If born, these mice survive for only days to weeks, and they exhibit widespread physical abnormalities, including severe impairment of epithelial development in multiple organ systems such as the gastrointestinal tract, lungs, brain, skin, eyes, kidneys, and liver.[4,11,14] There are defects in hair development, respiratory distress, retarded growth, and progressive wasting in these animals.[11] Conversely, activation of EGFR signaling via the administration of EGF enhanced the maturation of epithelial tissues in other murine studies, resulting in precocious eye opening and tooth eruption in newborn mice.[1]

These findings suggest that EGFR signaling plays an important role in multiple organ systems. Expression of EGFR has been documented in tissues of the digestive tract, skin, eyes, thymus, and respiratory, urogenital, and endocrine systems (Table 2). No detectable levels of EGFR have been found in skeletal tissue, lymph nodes, spleen, or the central nervous or cardiovascular systems.[11] Despite the ubiquity of EGFR, its role appears to be most important in the developing organism. The mitotic effects of exogenous EGF on mouse keratinocytes diminish with increasing age of the animal. The expression of EGFR on human skin cells also diminishes with age. In human fetal epidermis EGFR expression persists in all cell layers, whereas in adults there is limited distribution in normal skin.[15] Indeed, in adults, EGFR expression is found primarily on epithelial cells with the highest proliferative potential—namely the basal keratinocytes—consistent with its role as a regulator of normal skin growth.[11,15,16]


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