2008;60:416C425

2008;60:416C425. behavior of lung malignancy. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small Cyclosporine cell lung malignancy. These agents are generally better tolerated than standard chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancerCtargeted therapeutics. Ongoing research efforts in these areas as well as a conversation of emerging targeted agents being evaluated in clinical trials are the subjects of this review. mutation or amplification. Patients with SCLC are generally treated with chemotherapy and concurrent radiation (if staged as limited disease) or chemotherapy alone (if staged as considerable disease). TARGETED THERAPIES The term potentially applies to all malignancy treatments. Standard cytotoxic chemotherapy is usually targeted against DNA replication (alkylating brokers, topoisomerase inhibitors, anthracyclines, antimetabolites) or the mitotic microtubule apparatus (taxanes, vinca alkaloids). Recently, tumor expression of molecules relevant to the mechanism of standard chemotherapeutics (such as excision repair cross-complementation group 1, ribonucleotide reductase M1, and thymidylate synthase) has been associated with response to certain cytotoxic agents, thus providing further evidence of their targeted nature. However, currently in general clinical usage, targeted therapy refers to 2 classes of malignancy drugs: monoclonal antibodies (mAbs) and small-molecule TKIs. Usually, to achieve a favorable efficacy-to-toxicity profile where a therapy kills tumor but not normal cells, a molecular target should be either unique to, overexpressed in, or mutated in tumors, when compared with normal tissues. The majority of molecular targets are expressed on or within malignancy cells themselves. However, some targetsin particular, vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)are expressed in the tumor microenvironment or stroma. Compared with the dramatic benefit of imatinib therapy for chronic myeloid leukemia (CML),2 the overall effect of targeted therapy on lung malignancy outcomes has been modest to date. Only a minority of patients have tumors highly sensitive to these treatments. These cases generally develop resistance within months rather than years. In unselected populations, survival gains are measured in weeks. Molecular complexity and heterogeneity may account for the limitations of targeted therapy in lung malignancy and, indeed, in most malignancies. In contrast to the single, well-described chromosomal aberration of CML, lung malignancy cells are characterized by multiple molecular abnormalities.3 Furthermore, tumor genetic profiles differ markedly among patients, highlighting the importance of personalized or tailored therapy for this disease. MOLECULAR TARGETING OF NSCLC Oncogene activation (by gene amplification, point mutation, or DNA rearrangements) or loss of tumor suppressor gene (TSG) function (by loss of heterozygosity inactivating one allele and point mutation, epigenetic or transcription silencing inactivating the second allele)4,5 occurs in probably all lung cancers. This can result in dysregulation of signaling pathways, leading the cell to exhibit the hallmarks of malignancy (including self-sufficiency of growth signals, insensitivity to growth-inhibitory (anti-growth) signals, evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis).6,7 Research over the past decade has made a significant step forward by discovering oncogene addiction whereby the cell becomes dependent on this aberrant oncogenic signaling for survival.3,8C17 These driver oncogenes or oncogene addictions represent acquired conditional (around the oncogene) vulnerabilities in lung malignancy cells and present as significant therapeutic targets by offering specificity of killing tumor but not normal cells. Thus, the malignancy cell needs (is addicted to) the continued function of the oncogene (probably because of the associated acquired mutations that are required for the tumor cell to tolerate the oncogene), whereas normal cells do not need the continued function. This difference provides the therapeutic windows. In lung malignancy, generally activated oncogenes include EGFR/HER1/ERBB1, HER2/ERBB2, MYC, KRAS, MET, CCND1, CDK4, EML4-ALK fusion, and strongly correlated with sensitivity to EGFR TKIs.10,12 Exquisite sensitivity and marked tumor response have since been shown with TKIs (such as erlotinib and gefitinib) in EGFR mutant tumors10C12,35,36an example of oncogene dependency in lung malignancy where tumors initiated through EGFR mutation-activation of EGF signaling rely on continued EGF signaling for survival. Epidermal growth factor receptor Rabbit polyclonal to CREB1 mutation by either exon 19 deletion or exon 21 L858R mutation (termed classic mutations) each accounts for Cyclosporine approximately 45% of mutations and shows an increased amount and duration of EGFR activation compared with wild-type receptors10 Cyclosporine and has preferential activation of.