Epidermal Growth Factor Receptor Pathway

Erlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Currently, erlotinib, at a standard oral daily dose of 150 mg, is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients, however, it is being investigated in all stages of NSCLC. Erlotinib is well tolerated, with common toxicities including rash and diarrhoea. The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified. An important step has been made in the molecular characterization of potentially sensitive NSCLC patients. In fact, we have learned that activation, somatic EGFR gene mutations within the tyrosine kinase domain, are associated with a high possibility of a long lasting therapeutic response to erlotinib. The present review discusses the role of erlotinib in the treatment of NSCLC. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer diagnoses (1). The majority of people diagnosed with NSCLC are unsuitable for surgery since most patients have advanced disease at diagnosis. In recent decades, conventional treatments (surgery, chemotherapy, radiotherapy) have apparently reached a plateau of effectiveness in improving the outcomes of NSCLC patients, which still remain disappointing, especially in advanced stages (2), hence new treatment approaches have been developed. The epidermal growth factor receptor (EGFR) is one of the most studied targets for cancer therapy. The present review discusses the role of erlotinib, an anti-EGFR tyrosine kinase inhibitor (TKI), in the treatment of NSCLC. Epidermal Growth Factor Receptor Pathway The EGFR, also known as ErbB-1/HER1, is the first of four members of the ErbB family of cell membrane receptors, which are important mediators in cell growth, differentiation, and survival (3, 4). The EGFR is known to bind with a high affinity to several ligands including EGF, amphiregulin and transforming growth factor α (TGFα). NSCLC is characterized by a generally high expression, about 40-80%, of the EGFR family members of ligands and receptors (5). Two classes of EGFR antagonists have been successfully tested in phase III trials: anti-EGFR monoclonal antibodies (for example cetuximab) and small-molecule EGFR-TKIs (for example gefitinib and erlotinib). Both these two small molecules are administered orally, daily and inhibit EGFR activity by competing with adenosine triphosphate (ATP) for the ATP-binding site localized on the EGFR intracellular domain. The antitumour effects of EGFR inhibition in human cancer models are: inhibition of cancer cell proliferation with G0/G1 cell cycle arrest and, in some cases, induction of apoptosis; anti-angiogenesis through inhibition of angiogenic growth factor production; inhibition of invasion and metastases; potentation of antitumour activity of cytotoxic drugs and of radiotherapy (5). Several retrospective and prospective analyses revealed prognostic/predictive clinical and molecular factors related to the treatment with EGFR-TKIs, gefitinib and erlotinib (6, 7). In fact, the clinical predictors of response to EGFR-TKIs included female gender, adenocarcinoma histology, Asian ethnicity and particularly a history of never-smoking. The molecular predictors of activity are EGFR overexpression detected by immunohistochemistry (IHC), EGFR gene copy 1301 Correspondence to: Cesare Gridelli, MD, Division of Medical Oncology, “S.G. Moscati” Hospital, Contrada Amoretta, 8, 83100 Avellino, Italy. Tel: + 39 0825203573, Fax: + 39 0825203556, e-mail: [email protected]