Showing papers by "Susumu Kobayashi published in 2014"
TL;DR: Preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs) are provided and ongoing preclinical efforts for treating resistance have started to translate into patient care and hold promise to further boost the median survival of patients with EGFR mutations.
Abstract: Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.
105 citations
TL;DR: Activation of EGFR as a mechanism of resistance to crizotinib in preclinical models of ALK translocated NSCLC is identified, and the use of AlK plus EGFR TKIs could be explored for this important cohort of NSCLCs.
79 citations
TL;DR: It is shown that β-Catenin is essential for development of EGFR-mutated lung cancers and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.
Abstract: The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and development of EGFR tyrosine kinase inhibitors (TKIs) have revolutionized treatment for lung cancer. However, resistance to TKIs emerges in almost all patients and currently no effective treatment is available. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. β-catenin was upregulated and activated in EGFR mutated cells. Mutant EGFR preferentially bound to and tyrosine-phosphorylated β-catenin, leading to increase in β-catenin-mediated transactivation, particularly in cells harboring the gefitinib/erlotinib-resistant gatekeeper EGFR-T790M mutation. Pharmacological inhibition of β-catenin suppressed EGFR-L858R-T790M mutated lung tumor growth and genetic deletion of the β-catenin gene dramatically reduced lung tumor formation in EGFR-L858R-T790M transgenic mice. These data suggest that β-catenin plays an essential role in lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development or overcome resistance to EGFR TKIs.
79 citations
12 citations
TL;DR: The CC/M R is a practical and effective index for differentiating between ganglioneuromas and schwannomas in the mediastinum and is a useful index forDifferentiating between these neurogenic tumours.
Abstract: Objective:To evaluate the diagnostic value of the craniocaudal length (CC) to major axis ratio (CC/M R) for differentiating between schwannoma and ganglioneuroma in the mediastinum on CT/MRI.Methods:22 schwannomas (Group A: 7 schwannomas in the posterior mediastinum; Group B, 15 schwannomas located in the chest wall or regions of the mediastinum other than the posterior mediastinum) and 14 ganglioneuromas in the posterior mediastinum (Group C) were evaluated. For each tumour, the major and minor axes on the largest transaxial image and the CC were measured on CT/MRI. The CC/M R was calculated, and differences among the three groups were analysed.Results:The major axis, minor axis and CC measurements and CC/M R ranged from 23 to 52 mm (mean, 37 mm), 15 to 38 mm (28 mm), 25 to 62 mm (42 mm) and 0.66 to 1.4 mm (1.1 mm), respectively, in Group A; from 18 to 97 mm (37 mm), 10 to 71 mm (28 mm), 18 to 80 mm (35 mm) and 0.59 to 1.3 mm (0.95 mm), respectively, in Group B; and from 20 to 70 mm (49 mm), 15 to 60 mm ...
11 citations