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Monomerization of ALK Fusion Proteins as a Therapeutic Strategy in ALK-Rearranged Non-Small Cell Lung Cancers
https://asahikawa-med.repo.nii.ac.jp/records/2000265
https://asahikawa-med.repo.nii.ac.jp/records/2000265adfff913-1a4b-4615-8687-1b60a51513c0
| 名前 / ファイル | ライセンス | アクション |
|---|---|---|
O486 Hirai Noriko_TD.pdf (6.7 MB)
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| Item type | 学位論文 / Thesis or Dissertation_02(1) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 公開日 | 2021-09-29 | |||||||||||
| タイトル | ||||||||||||
| タイトル | Monomerization of ALK Fusion Proteins as a Therapeutic Strategy in ALK-Rearranged Non-Small Cell Lung Cancers | |||||||||||
| 言語 | en | |||||||||||
| 言語 | ||||||||||||
| 言語 | eng | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | EML4-ALK rearrangement | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | coiled-coil domain | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | lung cancer | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | oncogene fusion proteins | |||||||||||
| キーワード | ||||||||||||
| 言語 | en | |||||||||||
| 主題Scheme | Other | |||||||||||
| 主題 | peptide synthesis | |||||||||||
| 資源タイプ | ||||||||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_db06 | |||||||||||
| 資源タイプ | doctoral thesis | |||||||||||
| アクセス権 | ||||||||||||
| アクセス権 | open access | |||||||||||
| アクセス権URI | http://purl.org/coar/access_right/c_abf2 | |||||||||||
| その他（別言語等）のタイトル | ||||||||||||
| その他のタイトル | ALK陽性非小細胞肺癌におけるEML4-ALK融合蛋白の単量体化による治療戦略 | |||||||||||
| 言語 | ja | |||||||||||
| 著者 |
平井, 理子
× 平井, 理子
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| bibliographic_information |
en : Frontiers in oncology 号 10, p. 419-419, 発行日 2020-04-01 |
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| ISSN | ||||||||||||
| 収録物識別子タイプ | EISSN | |||||||||||
| 収録物識別子 | 2234-943x | |||||||||||
| DOI | ||||||||||||
| 関連タイプ | isIdenticalTo | |||||||||||
| 識別子タイプ | DOI | |||||||||||
| 関連識別子 | https://doi.org/10.3389/fonc.2020.00419 | |||||||||||
| 言語 | en | |||||||||||
| 関連名称 | 10.3389/fonc.2020.00419 | |||||||||||
| 識別番号 その他 | ||||||||||||
| 内容記述タイプ | Other | |||||||||||
| 内容記述 | PMID: 32300555 | |||||||||||
| 言語 | en | |||||||||||
| dissertation_number | ||||||||||||
| 学位授与番号 | 乙第486号 | |||||||||||
| 学位授与年月日 | ||||||||||||
| 学位授与年月日 | 2020-09-30 | |||||||||||
| 学位名 | ||||||||||||
| 言語 | ja | |||||||||||
| 学位名 | 博士（医学） | |||||||||||
| item_10_degree_grantor_32 | ||||||||||||
| 言語 | ja | |||||||||||
| 学位授与機関名 | 旭川医科大学 | |||||||||||
| item_10_description_33 | ||||||||||||
| 内容記述タイプ | Abstract | |||||||||||
| 内容記述 | Objective: Oncogenic echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion proteins found in non-small cell lung cancers (NSCLC) are constitutively phosphorylated and activated by dimerization via the coiled-coil domain (cc) within EML4. Here, we investigated whether disruption of ALK fusion protein oligomerization via competitive cc mimetic compounds could be a therapeutic strategy for EML4-ALK NSCLC. Methods: A Ba/F3 cell model was created that expressed an ALK intracellular domain in which the dimer/monomer state is ligand-regulated. This novel cell model was used to investigate the effect of disrupting ALK fusion protein oligomerization on tumor cell growth in vitro and in vivo using nude mice. Subsequently, the antiproliferative effects of endogenous cc domain co-expression and mimetic cc peptides were assayed in EML4-ALK cancer cell lines. Results: Cells induced to express monomeric ALK in vitro did not survive. When transplanted into mice, induction of monomers abrogated tumor formation. Using a fluorescent protein system to quantify protein-protein interactions of EML4-ALK and EML4cc, we demonstrated that co-expression of EML4cc suppressed EML4-ALK assembly concomitant with decreasing the rate of tumor growth in vitro and in vivo. In EML4-ALK cancer cell lines, administration of synthetic EML4cc peptide elicited a decrease of phosphorylation of ALK leading to reduction in tumor cell growth. Conclusions: Our findings support the monomerization of ALK fusion proteins using EML4cc peptides for competitive inhibition of dimerization as a promising therapeutic strategy for EML4-ALK NSCLC. Further studies are warranted to explore the use of specific cc peptide as a therapeutic option for other lung cancers harboring driver fusion genes containing a cc or oligomerization domain within the fusion partner. | |||||||||||
| 言語 | en | |||||||||||
| 出版タイプ | ||||||||||||
| 出版タイプ | VoR | |||||||||||
| 出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 | |||||||||||
