were stomatitis (32%), asthenia (11%), and diarrhea Only a small number of patients initially respond to first-generation EGFR inhibitors, and acquired resistance is common among those who respond. A number of mechanisms of resistance have been identified, but they do not account for all cases of resistance to treatment, suggesting that there are other unknown mechanisms of resistance. It appears that treatment resistance is pleomorphic and that many mechanisms can coexist in the same cell population. Therefore, combinations of therapies or therapies with multiple targets may be more effective. For next-generation EGFR TKIs, it will be important to determine whether acquired resistance still develops with the activation of compensatory signaling pathways. Many agents discussed herein are being evaluated in combination (e.g., an EGFR inhibitor in combination with a MET or mTOR inhibitor) in the hope that resistance mechanisms will be overcome by simultaneously silencing

EGFR signals and by blocking mechanisms of evasion. The strategy of targeting multiple tumorigenic pathways simultaneously (e.g., EGFR and VEGFR) may also be an effective approach to overcome resistance to current therapy. As our understanding of intra- and inter-EGFR family signaling increases, strategies for the development of targeted agents for the treatment of NSCLC will likely evolve. Financial support for medical and editorial assistance was provided by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). The author meets criteria for authorship as recommended by the International Selumetinib MEK inhibitor Committee of Medical Journal Editors (ICMJE), was fully responsible for all content and editorial decisions, and was involved in all stages of manuscript development. The author received no compensation related to the development of the manuscript. Small-molecule tyrosine kinase inhibitors (TKIs) of the human epidermal growth factor receptor (HER) include the reversible epidermal growth factor receptor (EGFR/ HER-1) inhibitors gefitinib and erlotinib. EGFR TKIs have demonstrated activity in the treatment of patients with non-small cell lung cancer (NSCLC)

harboring activating EGFR mutations; however, multiple mechanisms of resistance limit the benefit of these drugs. Although resistance to EGFR TKIs can be intrinsic and correlated with molecular lesions such as in Kirsten rat sarcoma viral oncogene homolog (KRAS; generally observed in a wild-type EGFR background), acquired resistance to EGFR TKIs can evolve in the setting of activating EGFR mutations, such as in the case of EGFR T790M mutations. Several irreversible inhibitors that target multiple members of the HER family simultaneously are currently in clinical development for NSCLC and may have a role in the treatment of TKI-sensitive and TKI-resistant disease. These include PF00299804, an inhibitor of EGFR/HER-1, HER-2, and HER-4, and afatinib (BIBW 2992), an inhibitor of EGFR/ HER-1, HER-2, and HER-4. Results of large, randomized trials of these agents may help to determine their potential for the treatment of NSCLC. The Oncologist 2011;16: 1498–1507 The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases (RTKs) is a well-established target for anticancer therapies. Composed of four members  Selumetinib

epidermal growth factor receptor (EGFR, HER-1, ErbB-1), HER-2 (ErbB- 2), HER-3 (ErbB-3), and HER-4 (ErbB-4)—theHERfamily controls various signaling pathways leading to cell growth, proliferation, differentiation, and survival throughout development and during adult physiologic homeostasis [1]. HER family ligands (e.g., EGF, transforming growth factor
, amphiregulin, epiregulin, b-cellulin, heparin-binding EGF) each bind to at least one HER family member [2]. Ligand binding leads to receptor dimerization and phosphorylation; homodimerization and heterodimerization among HER family members trigger cellular responses through signal diversification and amplification (Fig. 1) [3, 4]. Upon ligand-induced receptor d Selumetinib AZD6244