التفاصيل البيبلوغرافية
| العنوان: |
Monomerization of ALK Fusion Proteins as a Therapeutic Strategy in ALK-Rearranged Non-small Cell Lung Cancers |
| المؤلفون: |
Noriko Hirai, Takaaki Sasaki, Shunsuke Okumura, Yoshinori Minami, Shinichi Chiba, Yoshinobu Ohsaki |
| المصدر: |
Frontiers in Oncology, Vol 10 (2020) |
| بيانات النشر: |
Frontiers Media S.A., 2020. |
| سنة النشر: |
2020 |
| المجموعة: |
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: |
coiled-coil domain, EML4-ALK rearrangement, lung cancer, oncogene fusion proteins, peptide synthesis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: |
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. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2234-943X |
| Relation: |
https://www.frontiersin.org/article/10.3389/fonc.2020.00419/full; https://doaj.org/toc/2234-943X |
| DOI: |
10.3389/fonc.2020.00419 |
| URL الوصول: |
https://doaj.org/article/dcf0847cc19a4e1cbc193a0ee91d2f70 |
| رقم الانضمام: |
edsdoj.f0847cc19a4e1cbc193a0ee91d2f70 |
| قاعدة البيانات: |
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