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Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway
Although the utilization of selective BRAF(V600E) inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775054/ https://www.ncbi.nlm.nih.gov/pubmed/31578454 http://dx.doi.org/10.1038/s41598-019-50732-w |
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author | Gad, Shaimaa A. Ali, Hamdy E. A. Gaballa, Rofaida Abdelsalam, Rania M. Zerfaoui, Mourad Ali, Hamed I. Salama, Salwa H. Kenawy, Sanaa A. Kandil, Emad Abd Elmageed, Zakaria Y. |
author_facet | Gad, Shaimaa A. Ali, Hamdy E. A. Gaballa, Rofaida Abdelsalam, Rania M. Zerfaoui, Mourad Ali, Hamed I. Salama, Salwa H. Kenawy, Sanaa A. Kandil, Emad Abd Elmageed, Zakaria Y. |
author_sort | Gad, Shaimaa A. |
collection | PubMed |
description | Although the utilization of selective BRAF(V600E) inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAF(V600E) and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAF(V600E)- bearing melanoma cells. Dual targeting of CDC7 and BRAF(V600E) reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma. |
format | Online Article Text |
id | pubmed-6775054 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67750542019-10-09 Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway Gad, Shaimaa A. Ali, Hamdy E. A. Gaballa, Rofaida Abdelsalam, Rania M. Zerfaoui, Mourad Ali, Hamed I. Salama, Salwa H. Kenawy, Sanaa A. Kandil, Emad Abd Elmageed, Zakaria Y. Sci Rep Article Although the utilization of selective BRAF(V600E) inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAF(V600E) and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAF(V600E)- bearing melanoma cells. Dual targeting of CDC7 and BRAF(V600E) reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma. Nature Publishing Group UK 2019-10-02 /pmc/articles/PMC6775054/ /pubmed/31578454 http://dx.doi.org/10.1038/s41598-019-50732-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gad, Shaimaa A. Ali, Hamdy E. A. Gaballa, Rofaida Abdelsalam, Rania M. Zerfaoui, Mourad Ali, Hamed I. Salama, Salwa H. Kenawy, Sanaa A. Kandil, Emad Abd Elmageed, Zakaria Y. Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway |
title | Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway |
title_full | Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway |
title_fullStr | Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway |
title_full_unstemmed | Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway |
title_short | Targeting CDC7 sensitizes resistance melanoma cells to BRAF(V600E)-specific inhibitor by blocking the CDC7/MCM2-7 pathway |
title_sort | targeting cdc7 sensitizes resistance melanoma cells to braf(v600e)-specific inhibitor by blocking the cdc7/mcm2-7 pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775054/ https://www.ncbi.nlm.nih.gov/pubmed/31578454 http://dx.doi.org/10.1038/s41598-019-50732-w |
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