imerization, autophosphorylation of key tyrosine residues results in the stimulation of tyrosine kinase (TK) activity. HER- itself has no known ligand but possesses strong TK activity  and is the preferred binding partner for other HER receptors . HER- can bind ligand but has an inactive TK domain, so phosphorylation and subsequent downstream signaling occur only when dimerized with a partner (e.g., HER-) . Although HER- signaling in normal cells has been well characterized, its role in carcinogenesis is poorly NVP-BEZ235 understood. Numerous studies have indicated that aberrant signaling from the HER family of RTKs can lead to the development and progression of cancer –9, providing a rationale for targeting this family for cancer treatment. Drugs targeting the HER family play an important role in the management of many cancer types, including non-small cell lung cancer (NSCLC) , . This review discusses the clinical development of irreversible

U.S. Food and Drug Administration (FDA) in May 00 as monotherapy for patients with advanced NSCLC who failed to respond to conventional chemotherapy . However, phase III trials combining gefitinib with platinum-based chemotherapy (carboplatin plus paclitaxel or gemcitabine plus cisplatin) in chemotherapy-naive patients with advanced NSCLC (Iressa  NSCLC Trial Assessing Combination Therapy INTACT  and INTACT ) ,  failed to show an overall survival (OS) advantage with gefitinib, nor did a single-agent trial of gefitinib compared with placebo in previously treated patients (Iressa Survival Evaluation in Lung Cancer ISEL) . Based on these results, in 00 the U.S. FDA recommended a label restriction limiting continued gefitinib use to patients with advanced or metastatic NSCLC who had failed both platinum- and docetaxel-based chemotherapies who are benefiting or have benefited from gefitinib 9. Similarly, results from two large phase III trials of erlotinib in unselected chemotherapy-naive patients with advanced NSCLC (Tarceva  Lung Cancer Investigation TALENT and Tarceva Responses in Conjunction with Paclitaxel and Carboplatin TRIBUTE) failed to show a significantly longer OS time when used in combination with platinum-based chemotherapy purchase NVP-BEZ235

However, in the pivotal phase III BR. trial , single- agent erlotinib produced a significantly longer OS time than with placebo (. months versus . months; hazard ratio HR, 0.0; 9% confidence interval CI, 0. – 0.; p  .00) in previously treated patients with NSCLC. In November 00, erlotinib was approved by the U.S. FDA for the treatment of patients with locally advanced or metastatic NSCLC after the failure of at least one prior chemotherapy regimen . Based on results from the phase III Sequential Tarceva in Unresectable NSCLC (SATURN) trial, erlotinib is approved as maintenance therapy in the U.S. in patients with locally advanced or metastatic NSCLC whose disease has not progressed after four cycles of platinum-based therapy , . The landmark discovery that a subset of NSCLCs harbor activating mutations in the TK domain of EGFR elucidated the determinant of the dramatic responses observed in small percentages of patients treated with single-agent gefitinib or erlotinib  order NVP-BEZ235

These heterozygous somatic mutations most frequently consist of a point mutation within exon , leading to an amino acid substitution (e.g., LR) or in-frame deletions within exon 9. Kinase domain mutations lead to constitutive activation of EGFR by destabilization of the autoinhibited conformation of the receptor 9, 0. In mutant EGFR tumors, cell survival is dependent on EGFR signaling, a phenomenon termed “oncogene addiction” . Interestingly, although mutant EGFRs are constitutively activated, they possess lesser affinity for ATP . Furthermore, mutant EGFR binds gefitinib more tightly than wild-type EGFR; therefore, TKIs outcompete ATP in interactions with mutant EGFR, effectively