264 results on '"Yoshitaka Sekido"'
Search Results
252. Ectopic expression of c-kit in small-cell lung cancer
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Toyoaki Hida, Takashi Takahash, Toshitade Takahashi, Yoshitaka Sekido, Takahiko Sugiura, Yutaka Ariyoshi, Ryuzo Ueda, Kenji Hibi, and Ryohei Matsuda
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Adult ,Cancer Research ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Gene Expression ,Adenocarcinoma ,Biology ,Hematopoietic Cell Growth Factors ,Cell Line ,Fetus ,Reference Values ,Carcinoma, Non-Small-Cell Lung ,Proto-Oncogene Proteins ,Proto-Oncogenes ,Receptors, Colony-Stimulating Factor ,Parenchyma ,Gene expression ,Tumor Cells, Cultured ,medicine ,Humans ,RNA, Messenger ,Lung cancer ,Stem Cell Factor ,Cell growth ,Chemotaxis ,Receptor Protein-Tyrosine Kinases ,medicine.disease ,Recombinant Proteins ,In vitro ,respiratory tract diseases ,Proto-Oncogene Proteins c-kit ,Oncology ,Cell culture ,Carcinoma, Squamous Cell ,Cancer research ,Ectopic expression ,Stem cell ,Cell Division - Abstract
Accumulating evidence suggests that c-kit plays an important role in the regulation of growth of at least 3 lineages of stem cells, while only very limited data are available on the development of human solid tumors. Our recent studies have shown that c-kit transcripts are expressed in a very restricted sub-set of human solid tumors such as small-cell lung cancer (SCLC). We have also conducted an immunohistological study on in situ localization of the c-kit protein in various human solid tumors as well as in corresponding fetal and adult normal tissues. No c-kit expression was detected in normal bronchial epithelial cells or pneumocytes in lung parenchyma of human fetal and adult specimens, indicating that the c-kit protein is aberrantly expressed in lung-cancer cells. We also found that significant chemotactic response as well as moderate in vitro cell growth occurred in SCLC cell lines upon addition of recombinant human stem-cell factor.
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- 1994
253. 542 Abnormalities of FHIT and the FRA3B fragile site at 3p14.2 in lung cancer and associated preneoplastic lesions
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F. Rassool, John D. Minna, Adi F. Gazdar, Kwun M. Fong, Yoshitaka Sekido, Giuseppe Giaccone, E.J. Biesterveld, Ignacio I. Wistuba, Scott Bader, M. Ahmadian, Paul Zimmerman, Arvind K. Virmani, and S.T. Ong
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Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Chromosomal fragile site ,Cancer ,medicine.disease ,FHIT ,Internal medicine ,medicine ,Cancer research ,business ,Lung cancer - Published
- 1997
254. JBIR-23 and -24, Novel Anticancer Agents from Streptomycessp. AK-AB27.
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Keiichiro Motohashi, Ji-Hwan Hwang, Yoshitaka Sekido, Motoki Takagi, and Kazuo Shin-ya
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- 2009
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255. p53 apoptotic pathway molecules are frequently and simultaneously altered in nonsmall cell lung carcinoma.
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Shoichi Mori, Genshi Ito, Noriyasu Usami, Hiromu Yoshioka, Yuichi Ueda, Yoshinori Kodama, Masahide Takahashi, Kwun M. Fong, Kaoru Shimokata, and Yoshitaka Sekido
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- 2004
256. Loss of heterozygosity of chromosome 12p does not correlate with KRAS mutation in non-small cell lung cancer.
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Mika Uchiyama, Noriyasu Usami, Masashi Kondo, Shoichi Mori, Masao Ito, Genshi Ito, Hiromu Yoshioka, Munehisa Imaizumi, Yuichi Ueda, Masahide Takahashi, John D. Minna, Kaoru Shimokata, and Yoshitaka Sekido
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GENETIC mutation ,LUNG cancer ,CARCINOGENESIS - Abstract
Activating mutations of RAS gene families have been found in a variety of human malignancies, including lung cancer, suggesting their dominant role in tumorigenesis. However, several studies have shown a frequent loss of the wild-type KRAS allele in the tumors of murine models and an inhibition of oncogenic phenotype in tumor cell lines by transfection of wild-type RAS, indicating that wild-type RAS may have oncosuppressive properties. To determine whether loss of wild-type KRAS is involved in the development of human lung cancer, we investigated the mutations of KRAS, NRAS and BRAF in 154 primary non-small cell lung cancers (NSCLCs) as well as 10 NSCLC cell lines that have been shown to have KRAS mutations. We also determined the loss of heterozygosity status of KRAS alleles in these tumors. We detected point mutations of KRAS in 11 (7%) of 154 NSCLCs, with 10 cases at codon 12 and 1 at codon 61, but no mutations of NRAS or BRAF were found. Using the laser capture microdissection technique, we confirmed that 9 of the 11 tumors and 7 of the 10 NSCLC cell lines retained the wild-type KRAS allele. Among the cell lines with heterozygosity of mutant and wild-type KRAS, all of the cell lines tested for expression were shown to express more mutated KRAS than wild-type mRNA, with higher amounts of KRAS protein also being expressed compared to the cell lines with a loss of wild-type KRAS allele. In addition, among 148 specimens available for immunohistochemical analysis, 113 (76%) showed positive staining of KRAS, indicating that the vast majority of NSCLCs continue to express wild-type KRAS. Our findings indicate that the wild-type KRAS allele is occasionally lost in human lung cancer, and that the oncogenic activation of mutant KRAS is more frequently associated with an overexpression of the mutant allele than with a loss of the wild-type allele in human NSCLC development. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
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- 2003
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257. Telomerase activation and p53 mutations in urethane-induced A/J mouse lung tumor development
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Masahide Takahashi, Yoshitsugu Horio, Fuyuki Ishikawa, Joji Ohno, Jun-ichi Nishizawa, Yoshitaka Sekido, Yoshinori Hasegawa, Hidehiko Saito, and Kaoru Shimokata
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Cancer Research ,Telomerase ,Lung Neoplasms ,Protein subunit ,Mice, Inbred Strains ,Biology ,medicine.disease_cause ,Urethane ,Gene product ,Mice ,Telomerase RNA component ,Gene expression ,medicine ,Animals ,Telomerase reverse transcriptase ,RNA, Messenger ,Reverse Transcriptase Polymerase Chain Reaction ,General Medicine ,Genes, p53 ,Molecular biology ,Enzyme Activation ,Tumor progression ,Mutation ,Carcinogens ,Cancer research ,Carcinogenesis - Abstract
The mouse telomerase holoenzyme, which synthesizes telomeric DNA de novo, is a ribonucleoprotein complex that includes the mouse telomerase RNA component (mTERC), mouse telomerase-associated protein (mTEP1) and mouse telomerase reverse transcriptase (mTERT). To determine the role of telomerase in urethane-induced lung tumorigenesis in A/J mice we examined telomerase activity and the expression of each telomerase subunit in 20 tumor samples, harvested at 16, 28, 40 and 50 weeks after urethane treatment. The telomeric repeat amplification protocol assay showed that statistically significant telomerase activation occurred both early and late in tumorigenesis. Semi-quantitative reverse transcription-polymerase chain reaction analysis revealed that mRNA expression levels of mTEP1 and mTERT were up-regulated during tumor progression, while mTERC expression was not significantly different between tumors and normal lung. We further examined mTEP1 protein expression in normal lung tissue and lung tumors; western blot analysis showed preferential expression of mTEP1 protein in lung tumors compared with normal lung and immunohistochemistry revealed that a majority of the adenoma cells were positively stained in the nucleus, whereas only a few of the adjacent normal alveolar cells were immunoreactive. In addition, we investigated DNAs of the 20 tumor samples by single strand conformation polymorphism and sequencing analyses to examine whether alterations of the p53 gene in exons 5-8 were associated with telomerase activity. Although we found one nonsense, two missense, two silent and one simultaneous double mutation at different codons in six late stage tumors, there was no apparent correlation between telomerase activity and p53 mutations. Collectively, these results suggest that mTEP1 as well as mTERT may be involved in the regulation of telomerase activity and that telomerase activation may contribute to lung tumorigenesis in A/J mice independently of p53 gene alterations.
258. EGCG induces human mesothelioma cell death by inducing reactive oxygen species and autophagy
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Motohiko Satoh, Yukitoshi Takemura, Shunichiro Kubota, Hironobu Hamada, and Yoshitaka Sekido
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Mesothelioma ,Programmed cell death ,Cancer Research ,Apoptosis ,complex mixtures ,Autophagy ,medicine ,Genetics ,heterocyclic compounds ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,food and beverages ,Chloroquine ,medicine.disease ,Cell killing ,chemistry ,Oncology ,Cell culture ,Catalase ,Immunology ,biology.protein ,Cancer research ,sense organs ,Primary Research ,EGCG - Abstract
Malignant mesothelioma is an asbestos-related fatal disease with no effective cure. We studied whether a green tea polyphenol, epigallocathechin-3-gallate (EGCG), could induce cell death in five human mesothelioma cell lines. We found that EGCG induced apoptosis in all five mesothelioma cell lines in a dose-dependent manner. We further clarified the cell killing mechanism. EGCG induced reactive oxygen species (ROS), and impaired the mitochondrial membrane potential. As treatment with ROS scavengers, catalase and tempol, significantly inhibited the EGCG-induced apoptosis, ROS is considered to be responsible for the EGCG-induced apoptosis. Further, we found that EGCG induced autophagy, and that when autophagy was suppressed by chloroquine, the EGCG-induced cell death was enhanced. Taken together, these results suggest that EGCG has a great potential for the treatment of mesothelioma by inducing apoptosis and autophagy.
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259. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation.
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Toshihiko Yokoyama, Hirotaka Osada, Hideki Murakami, Yoshio Tatematsu, Tetsuo Taniguchi, Yutaka Kondo, Yasushi Yatabe, Yoshinori Hasegawa, Kaoru Shimokata, Yoshitsugu Horio, Toyoaki Hida, and Yoshitaka Sekido
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MESOTHELIOMA ,GENETIC regulation ,TUMOR suppressor proteins ,PHOSPHORYLATION ,BACTERIAL artificial chromosomes ,GENE amplification ,GENE expression ,ONCOGENES ,CELL lines - Abstract
We previously reported the results of bacterial artificial chromosome array comprehensive genomic hybridization of malignant pleural mesotheliomas (MPMs), including two cases with high-level amplification in the 11q22 locus. In this study, we found that the YAP1 gene encoding a transcriptional coactivator was localized in this amplified region and overexpressed in both cases, suggesting it as a candidate oncogene in this region. We analyzed the involvement of YAP1 in MPM proliferation, as well as its functional and physical interaction with Merlin encoded by the neurofibromatosis type 2 (NF2) tumor suppressor gene, which is frequently mutated in MPMs. YAP1-RNA interference suppressed growth of a mesothelioma cell line NCI-H290 with NF2 homozygous deletion, probably through cell-cycle arrest and apoptosis induction, whereas YAP1 transfection promoted the growth of MeT-5A, an immortalized mesothelial cell line. We also found that the introduction of NF2 into NCI-H290 induced phosphorylation at serine 127 of YAP1, which was accompanied by reduction of nuclear localization of YAP1, whereas nuclear localization of a YAP1 S 127A mutant was not affected. Furthermore, results of immunoprecipitation and in vitro pull-down assays indicated a physical interaction between Merlin and YAP1. These results suggest that YAP1 is involved in mesothelial cell growth and that the transcriptional coactivator activity of YAP1 is functionally inhibited by Merlin through the induction of phosphorylation and cytoplasmic retention of YAP1. This is the first report of negative regulatory signaling from Merlin to YAP1 in mammalian cells. Future studies of transcriptional targets of YAP1 in MPMs may shed light on the molecular mechanisms of MPM development and lead to new therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2008
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260. Variable DNA methylation patterns associated with progression of disease in hepatocellular carcinomas.
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Wentao Gao, Yutaka Kondo, Lanlan Shen, Yasuhiro Shimizu, Tsuyoshi Sano, Kenji Yamao, Atsushi Natsume, Yasuhiro Goto, Motokazu Ito, Hideki Murakami, Hirotaka Osada, Jiexin Zhang, Jean-Pierre J. Issa, and Yoshitaka Sekido
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DNA microarrays ,LIVER cancer ,METHYLATION ,DNA - Abstract
Hepatocellular carcinoma (HCC) most commonly arises from chronic inflammation due to viral infection, as a result of genetic and epigenetic abnormalities. A global picture of epigenetic changes in HCC is lacking. We used methylated CpG island amplification microarrays (MCAMs) to study 6458 CpG islands in HCC and adjacent preneoplastic tissues [chronic hepatitis (CH) or liver cirrhosis (LC)] in comparison with normal liver tissues where neither viral infection nor hepatitis has existed. MCAM identified 719 (11%) prominent genes of hypermethylation in HCCs. HCCs arising from LC had significantly more methylation than those arising from CH (1249 genes or 19% versus 444 genes or 7%, P < 0.05). There were four patterns of aberrant methylation: Type I (4%, e.g. matrix metalloproteinase 14) shows a substantially high methylation level in adjacent tissue and does not increase further in cancer. Type II (55%, e.g. RASSF1A) shows progressively increasing methylation from adjacent tissue to HCC. Type III (4%, e.g. GNA14) shows decreased methylation in adjacent tissue but either similar or increased methylation in HCC. Type IV (37%, e.g. CDKN2A) shows low levels of methylation in normal tissue and adjacent tissue but high levels in HCC. These DNA methylation changes were confirmed by quantitative pyrosequencing methylation analysis in representative 24 genes and were analyzed for correlation with clinicopathological parameters in 38 patients. Intriguingly, methylation in the Type IV genes is characteristic of moderately/poorly differentiated cancer. Our global epigenome analysis reveals distinct patterns of methylation that are probably to represent different pathophysiologic processes in HCCs. [ABSTRACT FROM AUTHOR]
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- 2008
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261. CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation.
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Kenichi Suda, Hiroshi Mizuuchi, Isao Murakami, Hidetaka Uramoto, Fumihiro Tanaka, Katsuaki Sato, Toshiki Takemoto, Takuya Iwasaki, Yoshitaka Sekido, Yasushi Yatabe, and Tetsuya Mitsudomi
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LUNG cancer patients , *LUNG cancer treatment , *GENE amplification , *EPIDERMAL growth factor receptors , *PROTEIN-tyrosine kinase inhibitors , *SOMATIC cells , *DRUG resistance - Abstract
Objectives Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs. Materials and methods We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined. Results and conclusion In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations. [ABSTRACT FROM AUTHOR]
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- 2014
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262. Chromatin Regulator PRC2 Is a Key Regulator of Epigenetic Plasticity in Glioblastoma.
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Atsushi Natsume, Motokazu Ito, Keisuke Katsushima, Fumiharu Ohka, Akira Hatanaka, Keiko Shinjo, Shinya Sato, Satoru Takahashi, Yuta Ishikawa, Ichiro Takeuchi, Hiroki Shimogawa, Motonari Uesugi, Hideyuki Okano, Kim, Seung U., Toshihiko Wakabayashi, Issa, Jean-Pierre J., Yoshitaka Sekido, and Yutaka Kondo
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TUMORS , *HETEROGENEITY , *GLIOMAS , *CHROMATIN , *RNA interference - Abstract
Tumor cell plasticity contributes to functional and morphologic heterogeneity. To uncover the underlying mechanisms of this plasticity, we examined glioma stem-like cells (GSC) where we found that the biologic interconversion between GSCs and differentiated non-GSCs is functionally plastic and accompanied by gain or loss of polycomb repressive complex 2 (PRC2), a complex that modifies chromatin structure. PRC2 mediates lysine 27 trimethylation on histone H3 and in GSC it affected pluripotency or development-associated genes (e.g., Nanog, Wnt1, and BMP5) together with alterations in the subcellular localization of EZH2, a catalytic component of PRC2. Intriguingly, exogenous expression of EZH2-dNLS, which lacks nuclear localization sequence, impaired the repression of Nanog expression under differentiation conditions. RNA interference (RNAi)-mediated attenuation or pharmacologic inhibition of EZH2 had little to no effect on apoptosis or bromodeoxyuridine incorporation in GSCs, but it disrupted morphologic interconversion and impaired GSC integration into the brain tissue, thereby improving survival of GSC-bearing mice. Pathologic analysis of human glioma specimens revealed that the number of tumor cells with nuclear EZH2 is larger around tumor vessels and the invasive front, suggesting that nuclear EZH2 may help reprogram tumor cells in close proximity to this microenvironment. Our results indicate that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity, which is required for the adaptation of glioblastoma cells to their microenvironment. Thus, PRC2-targeted therapy may reduce tumor cell plasticity and tumor heterogeneity, offering a new paradigm for glioma treatment. [ABSTRACT FROM AUTHOR]
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- 2013
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263. A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody.
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Shinji Abe, Yuki Morita, Mika Kato Kaneko, Masaki Hanibuchi, Yuta Tsujimoto, Hisatsugu Goto, Soji Kakiuchi, Yoshinori Aono, Jun Huang, Seidai Sato, Masatoshi Kishuku, Yuki Taniguchi, Mami Azuma, Kazuyoshi Kawazoe, Yoshitaka Sekido, Seiji Yano, Shin-ichi Akiyama, Saburo Sone, Kazuo Minakuchi, and Yukinari Kato
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MESOTHELIOMA , *GLYCOPROTEINS , *BLOOD platelet aggregation , *CELL-mediated cytotoxicity , *KILLER cells , *LABORATORY rats , *THERAPEUTICS - Abstract
Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a+) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM. [ABSTRACT FROM AUTHOR]
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- 2013
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264. EGFR-TKI Resistance Due to BIM Polymorphism Can Be Circumvented in Combination with HDAC Inhibition.
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Takayuki Nakagawa, Shinji Takeuchi, Tadaaki Yamada, Hiromichi Ebi, Takako Sano, Shigeki Nanjo, Daisuke Ishikawa, Mitsuo Sato, Yoshinori Hasegawa, Yoshitaka Sekido, and Seiji Yano
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EPIDERMAL growth factor receptors , *PEPTIDE receptors , *GENETIC polymorphism research , *HISTONE deacetylase inhibitors , *PROTEIN-tyrosine kinase inhibitors - Abstract
BIM (BCL2L11) is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGF receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in EGFR-mutant forms of non-small cell lung cancer (NSCLC). Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKIs gefitinib and erlotinib and therefore conferring an inherent drug-resistant phenotype. Indeed, patients with NSCLC, who harbored this host BIM polymorphism, exhibited significantly inferior responses to EGFR-TKI treatment than individuals lacking this polymorphism. In an attempt to correct this response defect in the resistant group, we investigated whether the histone deacetylase (HDAC) inhibitor vorinostat could circumvent EGFR-TKI resistance in EGFR-mutant NSCLC cell lines that also harbored the BIM polymorphism. Consistent with our clinical observations, we found that such cells were much less sensitive to gefitinib-induced apoptosis than EGFR-mutant cells, which did not harbor the polymorphism. Notably, vorinostat increased expression in a dose-dependent manner of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKI-resistant cells. In xenograft models, while gefitinib induced marked regression via apoptosis of tumors without the BIM polymorphism, its combination with vorinostat was needed to induce marked regression of tumors with the BIM polymorphism in the same manner. Together, our results show how HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR-mutant NSCLC where resistance to EGFR-TKI is associated with a common BIM polymorphism. [ABSTRACT FROM AUTHOR]
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- 2013
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