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So E.Y.,University of Chicago | Ausman M.,University of Chicago | Saeki T.,Saitama International Medical Center | Ouchi T.,University of Chicago
Cell Death and Disease | Year: 2011

DNA damage signaling pathways are initiated in response to chemical reagents and radiation damage, as well as in response to hypoxia. It is implicated that structural maintenance of chromosomes 1 (SMC1) is not only a component of the cohesion complex but also facilitates the activation of DNA damage checkpoint proteins. Here, we studied the mechanism of DNA damage checkpoint activated by ATR-SMC1 pathway when cells are treated with desferrioxamine (DFO), a hypoxia-mimetic reagent. We show that DFO treatment induces phosphorylation of SMC1 at Ser966, NBS1 at Ser343, Chk1 at Ser317, Chk2 at Thr68, and p53 at Ser15. Among these sites, phosphorylation of SMC1, NBS1, and Chk1 by DFO are mediated by ATR as it is greatly reduced in both ATR-deficient human fibroblasts and HCT116 human colon cancer cells in which ATR is heterozygously mutated, whereas these proteins are phosphorylated in cells deficient for ATM and DNA-PKcs. DFO-induced apoptosis is decreased in ATR-mutant HCT116 cells, although p53 is normally activated in those cells. Expression of SMC1 S966A in which Ser966 is substituted to Ala attenuates apoptosis and phosphorylation of Chk1 at Ser317 after DFO treatment, although levels of HIF1a are not significantly changed. These results suggest that DFO induces apoptosis through the ATR-SMC1 arm of the pathway. © 2011 Macmillan Publishers Limited All rights reserved. Source


Van Der Kloot W.A.,Leiden University | Kobayashi K.,Saitama International Medical Center | Yamaoka K.,University of Tokyo | Inoue K.,Saitama Cancer Center | And 2 more authors.
Journal of Psychosocial Oncology | Year: 2014

The intercorrelations among the 15 scales of the 30-item Core version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire suggest that one may combine (1) the physical functioning and role functioning scales, (2) the emotional functioning and cognitive functioning scales, and (3) the nine symptom scales. Together with the global health/quality of life scale and the social functioning scale, five measures remain. Principal component analysis of those five measures, using data from Japanese and Dutch breast and lung cancer patients, yielded two dimensions: (1) generalized health related quality of life and (2) health-independent psychological well-being. The correlations of these dimensions with the Brief Illness Perception Questionnaire and Karnofsky performance substantiated this interpretation. Copyright © 2014 Taylor & Francis Group, LLC. Source


Watanabe S.,Niigata University | Minegishi Y.,Infections Disease and Oncology | Yoshizawa H.,Niigata University | Maemondo M.,Miyagi Cancer Center | And 8 more authors.
Journal of Thoracic Oncology | Year: 2014

INTRODUCTION:: In non-small-cell lung cancer, an exon 19 deletion and an L858R point mutation in the epidermal growth factor receptor (EGFR) are predictors of a response to EGFR-tyrosine kinase inhibitors. However, it is uncertain whether other uncommon EGFR mutations are associated with sensitivity to EGFR-tyrosine kinase inhibitors. METHODS:: A post-hoc analysis to assess prognostic factors was performed with the use of patients with EGFR mutations (exon 19 deletion, L858R, G719X, and L861Q) who were treated with gefitinib in the NEJ002 study, which compared gefitinib with carboplatin-paclitaxel as the first-line therapy. RESULTS:: In the NEJ002 study, 225 patients with EGFR mutations received gefitinib at any treatment line. The Cox proportional hazards model indicated that performance status, response to chemotherapy, response to gefitinib, and mutation types were significant prognostic factors. Overall survival (OS) was significantly shorter among patients with uncommon EGFR mutations (G719X or L861Q) compared with OS of those with common EGFR mutations (12 versus 28.4 months; p = 0.002). In the gefitinib group (n = 114), patients with uncommon EGFR mutations had a significantly shorter OS (11.9 versus 29.3 months; p < 0.001). By contrast, OS was similar between patients with uncommon mutations and those with common mutations in the carboplatin-paclitaxel group (n = 111; 22.8 versus 28 months; p = 0.358). CONCLUSIONS:: The post-hoc analyses clearly demonstrated shorter survival for gefitinib-treated patients with uncommon EGFR mutations compared with the survival of those with common mutations and suggest that the first-line chemotherapy may be relatively effective for non-small-cell lung cancer with uncommon EGFR mutations. © 2013 by the International Association for the Study of Lung Cancer. Source


Shionome Y.,National University of Health Sciences | Yan L.,Roswell Park Cancer Institute | Liu S.,Roswell Park Cancer Institute | Saeki T.,Saitama International Medical Center | And 2 more authors.
PLoS ONE | Year: 2013

We have previously shown that mammary tumorigenesis in MMTV-Aurora-A mice is further enhanced when p53 is inactivated, demonstrating that integrity of p53 pathway determines phenotypes induced by this oncogenic kinase. In this study, we investigated the roles of genes involved in p53 pathway (p53, Puma, p21, Bax, and Chk2) in response to Aurora-A inhibitors, VX680 and MK-8745, and explored whether chemoresistant tumor cells would further undergo apoptosis with other therapeutic agents. Isogenic HCT116 cell lines were treated with VX680 or MK-8745. Cell cycle analysis, apoptosis, and tumorigenesity were studied. Chemoresistant cells were recovered from xenograft, and further induction of apoptosis was studied. Induction of apoptosis and aneuploidy with VX680 is much stronger than MK-8745. Xenograft assay indicates that tumor growth of HCT116 and HCT116 p53(-) cells are strongly inhibited by VX680, while that of other cell types are similarly inhibited by two compounds. Among the established cell lines recovered from xenografts, MK-8745-resistant clones contain elevated phosphorylation of mTOR and Akt. When further treated with inhibitors of both mTOR and Akt, those cells undergo apoptosis. These results indicate that p53-associated pathway plays a crucial role in regulating growth inhibition of tumor cells when treated with Aurora-A inhibitors. Combined treatment with Akt/mTOR inhibitors can further induce apoptosis of Aurora-A tumors. © 2013 Shionome et al. Source


Katakami N.,Kobe City Medical Center | Atagi S.,Kinki chuo Chest Medical Center | Goto K.,National Cancer Center Hospital East | Hida T.,Aichi Cancer Center Hospital | And 10 more authors.
Journal of Clinical Oncology | Year: 2013

Purpose New molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M. Patients and Methods This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after -12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progressionfree survival (PFS), overall survival (OS), and safety. Results Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R +T790M, and deletion in exon 19 T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatmentrelated AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease. Conclusion Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both. © 2013 by American Society of Clinical Oncology. Source

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