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Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid car...

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Autores principales: Audrito, Valentina, Moiso, Enrico, Ugolini, Filippo, Messana, Vincenzo Gianluca, Brandimarte, Lorenzo, Manfredonia, Ilaria, Bianchi, Simonetta, De Logu, Francesco, Nassini, Romina, Szumera-Ciećkiewicz, Anna, Taverna, Daniela, Massi, Daniela, Deaglio, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908704/
https://www.ncbi.nlm.nih.gov/pubmed/35272691
http://dx.doi.org/10.1186/s12967-022-03315-9
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author Audrito, Valentina
Moiso, Enrico
Ugolini, Filippo
Messana, Vincenzo Gianluca
Brandimarte, Lorenzo
Manfredonia, Ilaria
Bianchi, Simonetta
De Logu, Francesco
Nassini, Romina
Szumera-Ciećkiewicz, Anna
Taverna, Daniela
Massi, Daniela
Deaglio, Silvia
author_facet Audrito, Valentina
Moiso, Enrico
Ugolini, Filippo
Messana, Vincenzo Gianluca
Brandimarte, Lorenzo
Manfredonia, Ilaria
Bianchi, Simonetta
De Logu, Francesco
Nassini, Romina
Szumera-Ciećkiewicz, Anna
Taverna, Daniela
Massi, Daniela
Deaglio, Silvia
author_sort Audrito, Valentina
collection PubMed
description BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. METHODS: Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose–response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. RESULTS: The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. CONCLUSIONS: Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03315-9.
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spelling pubmed-89087042022-03-18 Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties Audrito, Valentina Moiso, Enrico Ugolini, Filippo Messana, Vincenzo Gianluca Brandimarte, Lorenzo Manfredonia, Ilaria Bianchi, Simonetta De Logu, Francesco Nassini, Romina Szumera-Ciećkiewicz, Anna Taverna, Daniela Massi, Daniela Deaglio, Silvia J Transl Med Research BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, is up-regulated in several cancers, including metastatic melanoma (MM). The BRAF oncogene is mutated in different cancer types, among which MM and thyroid carcinoma (THCA) are prominent. Drugs targeting mutant BRAF are effective, especially in MM patients, even though resistance rapidly develops. Previous data have linked NAMPT over-expression to the acquisition of BRAF resistance, paving the way for therapeutic strategies targeting the two pathways. METHODS: Exploiting the TCGA database and a collection of MM and THCA tissue microarrays we studied the association between BRAF mutations and NAMPT expression. BRAF wild-type (wt) cell lines were genetically engineered to over-express the BRAF V600E construct to demonstrate a direct relationship between over-activation of the BRAF pathway and NAMPT expression. Responses of different cell line models to NAMPT (i)nhibitors were studied using dose–response proliferation assays. Analysis of NAMPT copy number variation was performed in the TCGA dataset. Lastly, growth and colony forming assays were used to study the tumorigenic functions of NAMPT itself. RESULTS: The first finding of this work is that tumor samples carrying BRAF-mutations over-express NAMPT, as demonstrated by analyzing the TCGA dataset, and MM and THC tissue microarrays. Importantly, BRAF wt MM and THCA cell lines modified to over-express the BRAF V600E construct up-regulated NAMPT, confirming a transcriptional regulation of NAMPT following BRAF oncogenic signaling activation. Treatment of BRAF-mutated cell lines with two different NAMPTi was followed by significant reduction of tumor growth, indicating NAMPT addiction in these cells. Lastly, we found that several tumors over-expressing the enzyme, display NAMPT gene amplification. Over-expression of NAMPT in BRAF wt MM cell line and in fibroblasts resulted in increased growth capacity, arguing in favor of oncogenic properties of NAMPT. CONCLUSIONS: Overall, the association between BRAF mutations and NAMPT expression identifies a subset of tumors more sensitive to NAMPT inhibition opening the way for novel combination therapies including NAMPTi with BRAFi/MEKi, to postpone and/or overcome drug resistance. Lastly, the over-expression of NAMPT in several tumors could be a key and broad event in tumorigenesis, substantiated by the finding of NAMPT gene amplification. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-022-03315-9. BioMed Central 2022-03-10 /pmc/articles/PMC8908704/ /pubmed/35272691 http://dx.doi.org/10.1186/s12967-022-03315-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Audrito, Valentina
Moiso, Enrico
Ugolini, Filippo
Messana, Vincenzo Gianluca
Brandimarte, Lorenzo
Manfredonia, Ilaria
Bianchi, Simonetta
De Logu, Francesco
Nassini, Romina
Szumera-Ciećkiewicz, Anna
Taverna, Daniela
Massi, Daniela
Deaglio, Silvia
Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties
title Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties
title_full Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties
title_fullStr Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties
title_full_unstemmed Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties
title_short Tumors carrying BRAF-mutations over-express NAMPT that is genetically amplified and possesses oncogenic properties
title_sort tumors carrying braf-mutations over-express nampt that is genetically amplified and possesses oncogenic properties
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8908704/
https://www.ncbi.nlm.nih.gov/pubmed/35272691
http://dx.doi.org/10.1186/s12967-022-03315-9
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