6 results on '"Ryoko Okutani"'
Search Results
2. Supplementary materials from Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model
- Author
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Young Hak Kim, Toyohiro Hirai, Mitsuyoshi Ueda, Yuichi Sakamori, Hiroki Nagai, Yoshitaka Yagi, Hironori Yoshida, Koichi Hasegawa, Kiyoshi Uemasu, Takashi Nomizo, Yuto Yasuda, Ryoko Okutani, Hitomi Ajimizu, Yasushi Yoshimura, Koh Furugaki, Tomoko Funazo, Shunsuke Aburaya, Wataru Aoki, Hiroaki Ozasa, and Takahiro Tsuji
- Abstract
Supplementary Figure S1-S6 and Table S1-S3
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- 2023
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- View/download PDF
3. Data from Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model
- Author
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Young Hak Kim, Toyohiro Hirai, Mitsuyoshi Ueda, Yuichi Sakamori, Hiroki Nagai, Yoshitaka Yagi, Hironori Yoshida, Koichi Hasegawa, Kiyoshi Uemasu, Takashi Nomizo, Yuto Yasuda, Ryoko Okutani, Hitomi Ajimizu, Yasushi Yoshimura, Koh Furugaki, Tomoko Funazo, Shunsuke Aburaya, Wataru Aoki, Hiroaki Ozasa, and Takahiro Tsuji
- Abstract
The mechanisms responsible for the development of resistance to alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear, and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to alectinib, two patient-derived cell lines were established from an alectinib-naïve ALK-rearranged lung cancer and then after development of alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed. Coactivation of c-Src and MET was identified after the development of alectinib resistance. Combinatorial therapy against Src and MET significantly restored alectinib sensitivity in vitro (17.2-fold). Increased apoptosis, reduction of tumor volume, and inhibition of MAPK and PI3K/AKT signaling molecules for proliferation and survival were observed when the three kinases (Src, MET, and ALK) were inhibited. A patient-derived xenograft from the alectinib-resistant cells indicated that combination therapy with a saracatinib and crizotinib significantly decreased tumor size in vivo. To confirm the generality, a conventional alectinib-resistant cell line model (H2228-AR1S) was established from NCI-H2228 cells (EML4-ALK variant 3a/b). In H2228-AR1S, combination inhibition of Src and MET also restored alectinib sensitivity. These data reveal that dual salvage signaling from MET and Src is a potential therapeutic target in alectinib-resistant patients.Implications:This study demonstrates the feasibility to elucidate personalized drug-resistance mechanisms from individual patient samples.
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- 2023
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- View/download PDF
4. Data File S1 from Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model
- Author
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Young Hak Kim, Toyohiro Hirai, Mitsuyoshi Ueda, Yuichi Sakamori, Hiroki Nagai, Yoshitaka Yagi, Hironori Yoshida, Koichi Hasegawa, Kiyoshi Uemasu, Takashi Nomizo, Yuto Yasuda, Ryoko Okutani, Hitomi Ajimizu, Yasushi Yoshimura, Koh Furugaki, Tomoko Funazo, Shunsuke Aburaya, Wataru Aoki, Hiroaki Ozasa, and Takahiro Tsuji
- Abstract
Data sets of the phosphoproteome analysis in KTOR1 and KTOR1-RE cells
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- 2023
- Full Text
- View/download PDF
5. Alectinib Resistance in ALK-Rearranged Lung Cancer by Dual Salvage Signaling in a Clinically Paired Resistance Model
- Author
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Kiyoshi Uemasu, Koichi Hasegawa, Hiroki Nagai, Hiroaki Ozasa, Hironori Yoshida, Koh Furugaki, Takashi Nomizo, Wataru Aoki, Yuto Yasuda, Shunsuke Aburaya, Hitomi Ajimizu, Toyohiro Hirai, Takahiro Tsuji, Tomoko Funazo, Yuichi Sakamori, Ryoko Okutani, Yasushi Yoshimura, Mitsuyoshi Ueda, Yoshitaka Yagi, and Young Hak Kim
- Subjects
Male ,0301 basic medicine ,Alectinib ,Cancer Research ,Cell signaling ,Lung Neoplasms ,Carbazoles ,Mice, SCID ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,medicine ,Animals ,Humans ,Anaplastic lymphoma kinase ,Lung cancer ,Protein Kinase Inhibitors ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Crizotinib ,business.industry ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Female ,business ,Signal Transduction ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src - Abstract
The mechanisms responsible for the development of resistance to alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear, and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to alectinib, two patient-derived cell lines were established from an alectinib-naïve ALK-rearranged lung cancer and then after development of alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed. Coactivation of c-Src and MET was identified after the development of alectinib resistance. Combinatorial therapy against Src and MET significantly restored alectinib sensitivity in vitro (17.2-fold). Increased apoptosis, reduction of tumor volume, and inhibition of MAPK and PI3K/AKT signaling molecules for proliferation and survival were observed when the three kinases (Src, MET, and ALK) were inhibited. A patient-derived xenograft from the alectinib-resistant cells indicated that combination therapy with a saracatinib and crizotinib significantly decreased tumor size in vivo. To confirm the generality, a conventional alectinib-resistant cell line model (H2228-AR1S) was established from NCI-H2228 cells (EML4-ALK variant 3a/b). In H2228-AR1S, combination inhibition of Src and MET also restored alectinib sensitivity. These data reveal that dual salvage signaling from MET and Src is a potential therapeutic target in alectinib-resistant patients. Implications: This study demonstrates the feasibility to elucidate personalized drug-resistance mechanisms from individual patient samples.
- Published
- 2019
- Full Text
- View/download PDF
6. Abstract 1830: A clinical paired resistant model elucidated novel dual salvage signaling that confers alectinib resistance in ALK-rearranged lung cancer
- Author
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Takashi Nomizo, Takahiro Tsuji, Yasushi Yoshimura, Young Hak Kim, Mitsuyoshi Ueda, Toyohiro Hirai, Ryoko Okutani, Wataru Aoki, Koh Furugaki, Yuichi Sakamori, Kiyoshi Uemasu, Yuto Yasuda, Shunsuke Aburaya, Hiroaki Ozasa, Tomoko Funazo, Hironori Yoshida, and Hitomi Ajimizu
- Subjects
Alectinib ,Cancer Research ,Oncology ,business.industry ,medicine ,Cancer research ,Lung cancer ,medicine.disease ,business - Abstract
Conventional drug-resistant cancer cell line models have contributed to the elucidation of drug-resistant mechanisms. However, whether or not these models reflect patients in clinical settings is often controversial. We herein report a patient-derived drug resistant model system named the “clinical paired resistant model”. This model consists of 2 cell lines derived from a treatment-naïve patient (drug sensitive cell line model) and again after disease progression (drug resistant cell line model). The clinical paired resistant model of alectinib, the second generation ALK inhibitor, revealed the properties that cancer cells acquired during treatment using phosphoproteome and immunoblotting analyses; the proto-oncogene protein tyrosine kinase Src and hepatocyte growth factor receptor MET were activated after the development of alectinib resistance. No secondary mutations were detected in the coding region of ALK tyrosine kinase in the alectinib resistant model. In this alectinib-resistant model, the inhibition of Src and MET using saracatinib and PHA-665752 significantly restored alectinib sensitivity in vitro (17.2-fold change in IC50). Downstream signaling molecules for proliferation and survival, phosphorylation of Akt and ERK1/2, were inhibited and caspase 3/7 activity was significantly increased when the cells were treated with all three inhibitors (saracatinib, PHA-665752, and alectinib). Combined knockdown of SRC and MET restored alectinib sensitivity and inhibited downstream signaling in combination with ALK inhibition using alectinib, suggesting that the dual salvage signaling of MET and Src conferred alectinib resistance. A xenograft generated from our paired resistant model (N=5-6, in each group) indicated that combination therapy with a saracatinib and crizotinib, the first generation ALK inhibitor which also inhibits MET, significantly decreased tumor size in vivo as compared with saracatinib or crizotinib monotherapy. We also established a conventional alectinib resistant cell line model in vitro by exposing NCI-H2228 cells (EML4-ALK variant 3a/b) to 300 nM of alectinib for 3 months and found MET and Src were also activated in the model. Our clinical paired resistant model permits the detection of drug-resistant mechanisms without exploring the common characteristics of numerous drug-resistant patients. Our results demonstrate that MET and Src are potential therapeutic targets in patients with alectinib resistance and that the clinical paired resistant model may be a new strategy to elucidate drug-resistant mechanisms in relatively rare cancers. Citation Format: Takahiro Tsuji, Hiroaki Ozasa, Takashi Nomizo, Tomoko Funazo, Yuto Yasuda, Yuichi Sakamori, Hironori Yoshida, Kiyoshi Uemasu, Hitomi Ajimizu, Ryoko Okutani, Shunsuke Aburaya, Wataru Aoki, Mitsuyoshi Ueda, Koh Furugaki, Yasushi Yoshimura, Toyohiro Hirai, Young Hak Kim. A clinical paired resistant model elucidated novel dual salvage signaling that confers alectinib resistance in ALK-rearranged lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1830.
- Published
- 2018
- Full Text
- View/download PDF
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