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Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells

SIMPLE SUMMARY: Compelling evidence has shown that cancer stem cells (CSCs) are responsible for high resistance to conventional anti-cancer therapies. Here, we demonstrate that the tumor microenvironment protects CR-CSCs from EGFR/HER2, BRAF and PI3K targeting, promoting CD44v6 and Myc expression. A...

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Autores principales: Gaggianesi, Miriam, Mangiapane, Laura Rosa, Modica, Chiara, Pantina, Vincenzo Davide, Porcelli, Gaetana, Di Franco, Simone, Lo Iacono, Melania, D’Accardo, Caterina, Verona, Francesco, Pillitteri, Irene, Turdo, Alice, Veschi, Veronica, Brancato, Ornella Roberta, Muratore, Giampaolo, Pistone, Giuseppe, Bongiorno, Maria Rita, Todaro, Matilde, De Maria, Ruggero, Stassi, Giorgio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833549/
https://www.ncbi.nlm.nih.gov/pubmed/35158939
http://dx.doi.org/10.3390/cancers14030673
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author Gaggianesi, Miriam
Mangiapane, Laura Rosa
Modica, Chiara
Pantina, Vincenzo Davide
Porcelli, Gaetana
Di Franco, Simone
Lo Iacono, Melania
D’Accardo, Caterina
Verona, Francesco
Pillitteri, Irene
Turdo, Alice
Veschi, Veronica
Brancato, Ornella Roberta
Muratore, Giampaolo
Pistone, Giuseppe
Bongiorno, Maria Rita
Todaro, Matilde
De Maria, Ruggero
Stassi, Giorgio
author_facet Gaggianesi, Miriam
Mangiapane, Laura Rosa
Modica, Chiara
Pantina, Vincenzo Davide
Porcelli, Gaetana
Di Franco, Simone
Lo Iacono, Melania
D’Accardo, Caterina
Verona, Francesco
Pillitteri, Irene
Turdo, Alice
Veschi, Veronica
Brancato, Ornella Roberta
Muratore, Giampaolo
Pistone, Giuseppe
Bongiorno, Maria Rita
Todaro, Matilde
De Maria, Ruggero
Stassi, Giorgio
author_sort Gaggianesi, Miriam
collection PubMed
description SIMPLE SUMMARY: Compelling evidence has shown that cancer stem cells (CSCs) are responsible for high resistance to conventional anti-cancer therapies. Here, we demonstrate that the tumor microenvironment protects CR-CSCs from EGFR/HER2, BRAF and PI3K targeting, promoting CD44v6 and Myc expression. Alternatively, as a substitution for HER2 and BRAF, the Myc transcription inhibitor can overcome the protective effects of microenvironmental cytokines, impairing the survival of CR-CSCs. These data highlight the targeting of Myc and PI3K activity as a novel therapeutic strategy against advanced colorectal cancer. ABSTRACT: Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression.
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spelling pubmed-88335492022-02-12 Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells Gaggianesi, Miriam Mangiapane, Laura Rosa Modica, Chiara Pantina, Vincenzo Davide Porcelli, Gaetana Di Franco, Simone Lo Iacono, Melania D’Accardo, Caterina Verona, Francesco Pillitteri, Irene Turdo, Alice Veschi, Veronica Brancato, Ornella Roberta Muratore, Giampaolo Pistone, Giuseppe Bongiorno, Maria Rita Todaro, Matilde De Maria, Ruggero Stassi, Giorgio Cancers (Basel) Article SIMPLE SUMMARY: Compelling evidence has shown that cancer stem cells (CSCs) are responsible for high resistance to conventional anti-cancer therapies. Here, we demonstrate that the tumor microenvironment protects CR-CSCs from EGFR/HER2, BRAF and PI3K targeting, promoting CD44v6 and Myc expression. Alternatively, as a substitution for HER2 and BRAF, the Myc transcription inhibitor can overcome the protective effects of microenvironmental cytokines, impairing the survival of CR-CSCs. These data highlight the targeting of Myc and PI3K activity as a novel therapeutic strategy against advanced colorectal cancer. ABSTRACT: Despite advances in the curative approach, the survival rate of advanced colorectal cancer (CRC) patients is still poor, which is likely due to the emergence of cancer cell clones resistant to the available therapeutic options. We have already shown that CD44v6-positive CRC stem cells (CR-CSCs) are refractory toward standard anti-tumor therapeutic agents due to the activation of the PI3K pathway together with high HER2 expression levels. Tumor microenvironmental cytokines confer resistance to CR-CSCs against HER2/PI3K targeting by enhancing activation of the MAPK pathway. Here, we show that the CSC compartment, spared by BRAF inhibitor-based targeted therapy, is associated with increased expression levels of CD44v6 and Myc and retains boosted clonogenic activity along with residual tumorigenic potential. Inhibition of Myc transcription, downstream of the MAPK cascade components, and PI3K pathway activity was able to overcome the protective effects of microenvironmental cytokines, affecting the survival and the clonogenic activity of CR-CSCs, regardless of their mutational background. Likewise, the double targeting induced stabilization of mouse tumor avatars. Altogether, these data outline the rationale for dual kinase targeting of CR-CSCs to prevent their adaptive response, which would lead to disease progression. MDPI 2022-01-28 /pmc/articles/PMC8833549/ /pubmed/35158939 http://dx.doi.org/10.3390/cancers14030673 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gaggianesi, Miriam
Mangiapane, Laura Rosa
Modica, Chiara
Pantina, Vincenzo Davide
Porcelli, Gaetana
Di Franco, Simone
Lo Iacono, Melania
D’Accardo, Caterina
Verona, Francesco
Pillitteri, Irene
Turdo, Alice
Veschi, Veronica
Brancato, Ornella Roberta
Muratore, Giampaolo
Pistone, Giuseppe
Bongiorno, Maria Rita
Todaro, Matilde
De Maria, Ruggero
Stassi, Giorgio
Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
title Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
title_full Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
title_fullStr Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
title_full_unstemmed Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
title_short Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells
title_sort dual inhibition of myc transcription and pi3k activity effectively targets colorectal cancer stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833549/
https://www.ncbi.nlm.nih.gov/pubmed/35158939
http://dx.doi.org/10.3390/cancers14030673
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