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EGF denotes epidermal growth factor; HB, heparin-binding; NRG, neuregulin; bFGF, basic fibroblast growth factor; P, phosphate; TGF, transforming growth factor.
Adapted from Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160-1174.
The epidermal growth factor receptor (EGFR) is the prototypical receptor tyrosine kinase (RTK) and one of the most comprehensively studied molecular targets in clinical oncology. Therapeutic agents specifically targeting EGFR have shown highly promising activity in the clinic.
However, resistance to these agents and the question of which patients are most likely to derive therapeutic benefit from them have posed significant challenges to their optimal use. A greater understanding of the molecular mechanisms underlying EGFR signaling is now beginning to stimulate the development of new diagnostic and therapeutic strategies to enhance the impact of EGFR-targeted therapies.
The Prototypical Tyrosine Kinase
EGFR was the first of the RTKs to be identified, following the Nobel Prize-winning discovery of its principal ligand EGF in the early 1960s. It is a member of the ERBB family of receptors and can be activated by numerous other ligands besides EGF, including transforming growth factor (TGF) α.
As with other members of the ERBB family, ligand binding drives the formation of receptor pairs, either between 2 EGFR molecules or between EGFR and another member of the family (homo-/heterodimerization), which stimulates the intrinsic tyrosine kinase activity of the receptor. Among the key intracellular signal transduction cascades subsequently activated by the EGFR are the MAPK cascade and the phosphatidylinositol 3-kinase/ protein kinase B (PI3K/Akt) cascade.
Under normal conditions, EGFR activation is tightly regulated by the availability of the ligand. Dysregulation of the EGFR pathway by overexpression or constitutive activation can promote 5 of the 6 hallmarks of cancer. Defects in the EGFR signaling pathway have now been implicated in a diverse range of cancers, including colorectal, head and neck, lung, breast, and pancreatic cancers.
Epidermal growth factor receptor (EGFR) tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib (Tarceva). Surface (gray) of EGFR and kinase; Tarceva in ball-and-stick (carbon-green, oxygen-red, nitrogen-blue).
EGFR-specific treatments that have been developed thus far fall into 2 distinct categories: (1) small-molecule tyrosine kinase inhibitors (TKIs) that block the adenosine triphosphate (ATP)-binding site and prevent tyrosine kinase activity; and (2) monoclonal antibodies that block extracellular ligand binding. Four of these agents are currently approved by the FDA.
Gefitinib (Iressa, AstraZeneca) was the first EGFR-specific TKI to be introduced and was originally fast-tracked for FDA approval in 2003 for the treatment of patients with non-small cell lung cancer (NSCLC). Following its subsequent poor performance in the INTACT 1 and 2 phase III trials, which showed no improvement in overall survival (OS) or time to progression (TTP) in the first-line setting, the FDA limited the indication for gefitinib to patients who are currently or have previously benefited from gefitinib.
A second TKI, erlotinib (Tarceva, Genentech), was approved in 2004 as a monotherapy for patients with NSCLC, and subsequently in combination with gemcitabine for advanced pancreatic cancer in 2005.
Two monoclonal antibodies, cetuximab (Erbitux, Bristol-Myers Squibb), a chimeric mouse/human antibody, and panitumumab (Vectibix, Amgen), a fully humanized antibody, are currently approved for the treatment of metastatic colorectal cancer. Cetuximab is also approved for the treatment of recurrent head and neck cancers.
Lapatinib (Tykerb, GlaxoSmithKline) and vandetanib (Caprelsa, AstraZeneca) are FDAapproved, multitargeted TKIs that include EGFR among their targets.
Other agents under development include the TKI afatinib (Boehringer Ingelheim) and the monoclonal antibody nimotuzumab (YM BioSciences Inc). Phase I trials of a recombinant antibody, Sym004 (Symphogen), a 1:1 mixture of 2 chimeric anti-EGFR antibodies, were also reported at the 2011 American Society of Clinical Oncology (ASCO) meeting.