Retrospective Analysis Of Ipass

By: john

In the past few years, the seminal discovery of activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene has brought great revolution for the treatment of non-small cell lung cancer (NSCLC). While the first EGFR tyrosine kinase inhibitors (gefitinib, erlotinib) were approved for use in NSCLC prior to the knowledge of activating EGFR mutations, the clinical use of EGFR tyrosine kinase blockers has been optimized after the found of EGFR mutations and heralded the era of molecular targeted therapy in NSCLC. Retrospective analysis of IPASS (Iressa Pan-Asia Study) clearly proved that the presence or absence of EGFR mutations in Asian never-smokers/light former smokers statistically confirmes the presence or lack of response to EGFR tyrosine kinase inhibitors, respectively. Several prospective randomized trials have now determined the ustility of EGFR tyrosine kinase inhibitors in patients with advanced treatment-nave NSCLC with EGFR mutations markedly ameliorated the response rate and progression-free survival compared with standard platinum-based chemotherapy. The characterization of NSCLC patients with activating EGFR mutations provided the bulk of the molecular under-pinning of the seminal observation that NSCLC in neversmokers is a distinct clinical entity. However, as demonstrated by IPASS, even among a clinically defined NSCLC patient cohort only slightly more than half of these patients harbored activating EGFR mutations and that other driver mutations remained to be discovered in NSCLC.

The discovery of anaplastic lymphoma kinase (ALK)

Anaplastic lymphoma kinase (ALK) is thus named because it was first discovered to be translocated in anaplastic large cell lymphoma. Since the late 1980s, changes in the ALK gene have been well recognized as playing a critical role in the pathogenesis of anaplastic large cell lymphoma, a subset of B cell non-Hodgkins lymphoma, inflammatory myofibro-blastic tumors, and in neuroblastoma. However, perturbations in the ALK gene had not been discovered in common solid tumors until two groups independently reported the found of ALK rearrangement in NSCLC in 2007. A cDNA library derived from adenocarcinoma of the lung of a 62-year-old male Japanese smoker for transforming activity was screened. This fusion arises from an intrachromosomal inversion on the short arm of chromosome 2 [Inv (2)(p21p23)] that joins exons 113 of the echinoderm microtubule-associated protein-like 4 gene (EML4) to exons 2029 of ALK. The resulting chimeric protein, EML4-ALK, contains an N terminus derived from EML4 and a C terminus containing the entire intracellular tyrosine kinase domain of ALK. Since the initial discovery of this fusion, multiple other variants of EML4-ALK have been published, all of which encode the same cytoplasmic portion of ALK but contain different truncations of EML4. Additionally, other fusion partners with ALK have been described (TFG and KIF5B), but these fusion variants are much less common than EML4-ALK. The various fusion partners of ALK regulate ligand-independent dimerization of ALK leading to constitutive kinase activity. EML4-ALK possesses potent oncogenic activity in cell cultures. In transgenic mouse models, lung-specific expression of EML4-ALK results in development of numerous lung adenocarcinoma. Therapy of EML4-ALK transgenic mice with ALK inhibitors likewise leads to tumor regression. Meanwhile, in an independent study, Rikova et al detertemined the same EML4-ALK translocation in NSCLC while searching for candidate tyrosine kinases in NSCLC by screening for phosphotyrosine activation in 150 NSCLC tumors as well as 41 NSCLC cell lines. They verified kinases known to have a dominant role in NSCLC pathogenesis, such as EGFR and mesenchymal-epithelial transition (MET) receptor tyrosine kinase, as well as others not previously involved in NSCLC, including platelet-derived growth factor receptor-? and ROS. The samples with ALK hyperphosphorylation were shown to harbor EML4-ALK (three cases) or TFG-ALK (one case). [1]

Properties of anaplastic lymphoma kinase (ALK)

ALK belongs to the leukocyte tyrosine kinase receptor superfamily. ALK is a single-chain transmembrane receptor. The extracellular domain contains an N-terminal signal peptide sequence and is the ligand-binding site for the activating ligands of ALK, pleiotrophin, and midkine. This is followed by the transmembrane and juxtamembrane region which contains a binding site for phosphotyrosine-dependent interaction with insulin receptor substrate-1. The final section has an intracellular tyrosine kinase domain with three phosphorylation sites (Y1278, Y1282, and Y1283), followed by the C-terminal domain with interaction sites for phospholipase C-gamma and Src homology 2 domain-containing SHC. The signaling pathways involving ALK have recently been the subject of an expert review.

Met inhibitors

Simultaneous with the discovery of ALK-rearranged NSCLC, crizotinib, a multitargeted receptor tyrosine kinase inhibitor, had been carried out early Phase I clinical development primarily as a MET inhibitor. With the ability of a few Phase I clinical sites to develop and standardize a breakapart fluorescence in situ hybridization (FISH) assay for ALK-rearranged NSCLC, there was a concerted switch in the focus of the Phase I crizotinib trial when the first two ALK-rearranged NSCLC patients derived clinical benefit from crizotinib.[2] Other MET inhibitors include, PF-04217903, axitinib and foretinib, et al.

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Retrospective Analysis Of Ipass

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