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Fujiwara T.,Tokyo University of Science | Hiramatsu M.,The Cancer Institute | Isagawa T.,Tokyo University of Science | Ninomiya H.,The Cancer Institute | And 12 more authors.
Lung Cancer | Year: 2012

Background: Lung adenocarcinoma is heterogeneous regarding histology, etiology and prognosis. Although there have been several attempts to find a subgroup with poor prognosis, it is unclear whether or not adenocarcinoma with neuroendocrine (NE) nature has unfavorable prognosis. Materials and methods: To elucidate whether a subtype of adenocarcinoma with NE nature has poor prognosis, we performed gene expression profiling by cDNA microarray for 262 Japanese lung cancer and 30 normal lung samples, including 171 adenocarcinomas, 56 squamous cell carcinomas and 35 NE tumors. A co-expression gene set with ASCL1, an NE master gene, was utilized to classify tumors by non-negative matrix factorization, followed by validation using an ASCL1 knock-down gene set in DMS79 cells as well as an independent cohort (n= 139) derived from public microarray databases as a test set. Results: The co-expression gene set classified the adenocarcinomas into alveolar cell (AL), squamoid, and NE subtypes. The NE subtype, which clustered together almost all the NE tumors, had significantly poorer prognosis than the AL subtype that clustered with normal lung samples (p= 0.0075). The knock-down gene set also classified the 171 adenocarcinomas into three subtypes and this NE subtype also had the poorest prognosis. The co-expression gene set classified the independent database-derived American cohort into two subtypes, with the NE subtype having poorer prognosis. None of the single NE gene expression was found to be linked to survival difference. Conclusion: Co-expression gene set with ASCL1, rather than single NE gene expression, successfully identifies an NE subtype of lung adenocarcinoma with poor prognosis. © 2011 Elsevier Ireland Ltd. Source

Yoneya T.,Kamakura Research Laboratories | Taniguchi K.,Kamakura Research Laboratories | Nakamura R.,Kamakura Research Laboratories | Tsunenari T.,Kamakura Research Laboratories | And 5 more authors.
Anticancer Research | Year: 2010

Background: Tamoxifen, a selective estrogen receptor modulator, and fulvestrant, a selective estrogen receptor down-regulator (SERD), are now available for estrogen receptor-positive breast cancer patients. However, these patients acquire drug-resistance during the treatments. We identified a new orally active nonsteroidal SERD, CH4986399, which is structurally unrelated to fulvestrant and tamoxifen. Materials and Methods: We examined the oral antitumor activity and down-regulation of ER by CH4986399 in human breast cancer Br-10 and ZR-75-1 xenografts. Results: In the Br-10 xenografts, CH4986399 (100 mg/kg p.o.) as well as fulvestrant (3 mg/body s.c.) strongly reduced tumor weight. In the ZR-75-1 xenografts, CH4986399 (100 mg/kg p.o.) strongly reduced tumor weight and ER content without agonistic activity. In contrast, tamoxifen (100 mg/kg p.o.) showed only moderate antitumor activity and no ER down-regulation. Conclusion: With a chemical structure different from both fulvestrant and tamoxifen, CH4986399, may help overcome drug resistance from the endocrine treatment sequence for breast cancer patients. Source

Furugaki K.,Kamakura Research Laboratories | Iwai T.,Kamakura Research Laboratories | Moriya Y.,Kamakura Research Laboratories | Harada N.,Kamakura Research Laboratories | Fujimoto-Ouchi K.,Kamakura Research Laboratories
Lung Cancer | Year: 2014

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) show notable effects against non-small cell lung cancers (NSCLCs) harboring EGFR-activating mutations. However, almost all patients eventually acquire resistance to EGFR-TKIs. In this study, we established novel erlotinib resistant NSCLC cells and examined their resistant mechanisms. Resistant cells were established in 14, 3, and 0 wells exposed to 0.1, 1, and 10μM erlotinib, respectively. The IC50 values of these cells were 47- to 1209-fold higher than that of the parent cells. No secondary T790M mutation was detected in any resistant cells. However, in 13/17 resistant cells, EGFR copy number was reduced less than approximately one-eighth of parent cells, and in one resistant cell (B10), >99.99% of the population was EGFR-unamplified cells. Most (97.5%) parent cells showed EGFR amplification, but 2.5% of the population comprised EGFR-unamplified cells. An EGFR-unamplified clone (4D8) isolated from parent cells in erlotinib-free normal medium also showed erlotinib resistance comparable to the resistant B10 cells. Loss of an EGFR-amplified chromosome 7 (EGFR-ampch7) was observed in 4D8 and B10 cells. EGFR-unamplified cells were constantly maintained as a minor population of the parent cells under normal cell culture conditions. In conclusion, loss of an EGFR-ampch7 causes acquired resistance in EGFR-mutated HCC827 cells exposed to a relatively low concentration of erlotinib, but a high concentration prevents the emergence of resistance. © 2013 The Authors. Source

Furugaki K.,Kamakura Research Laboratories | Fukumura J.,Kamakura Research Laboratories | Iwai T.,Kamakura Research Laboratories | Yorozu K.,Kamakura Research Laboratories | And 8 more authors.
International Journal of Cancer | Year: 2016

Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL. What's new? A new drug combo may enhance lung cancer treatment. Patients whose lung cancers have a mutation in EGFR often respond well to EGFR tyrosine kinase inhibitors, such as erlotinib. However, within a few years, they develop resistance, and the treatment falters. Supplementing the erlotinib with bevacizumab, an antibody against VEGF, extends the patients' progression-free survival. This study investigated how bevacizumab effects this improvement. Using lung tumors growing in mice, the authors showed that the two-pronged attack did not help if tumors were already resistant to erlotinib, but if erlotinib suppressed the tumors' growth, then bevacizumab enhanced the tumor inhibition. © 2015 UICC. Source

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