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PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
OBJECTIVE: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666826/ https://www.ncbi.nlm.nih.gov/pubmed/33436496 http://dx.doi.org/10.1136/gutjnl-2020-323553 |
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author | Mangiapane, Laura Rosa Nicotra, Annalisa Turdo, Alice Gaggianesi, Miriam Bianca, Paola Di Franco, Simone Sardina, Davide Stefano Veschi, Veronica Signore, Michele Beyes, Sven Fagnocchi, Luca Fiori, Micol Eleonora Bongiorno, Maria Rita Lo Iacono, Melania Pillitteri, Irene Ganduscio, Gloria Gulotta, Gaspare Medema, Jan Paul Zippo, Alessio Todaro, Matilde De Maria, Ruggero Stassi, Giorgio |
author_facet | Mangiapane, Laura Rosa Nicotra, Annalisa Turdo, Alice Gaggianesi, Miriam Bianca, Paola Di Franco, Simone Sardina, Davide Stefano Veschi, Veronica Signore, Michele Beyes, Sven Fagnocchi, Luca Fiori, Micol Eleonora Bongiorno, Maria Rita Lo Iacono, Melania Pillitteri, Irene Ganduscio, Gloria Gulotta, Gaspare Medema, Jan Paul Zippo, Alessio Todaro, Matilde De Maria, Ruggero Stassi, Giorgio |
author_sort | Mangiapane, Laura Rosa |
collection | PubMed |
description | OBJECTIVE: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy. DESIGN: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance. RESULTS: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy. CONCLUSIONS: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting. |
format | Online Article Text |
id | pubmed-8666826 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-86668262021-12-28 PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells Mangiapane, Laura Rosa Nicotra, Annalisa Turdo, Alice Gaggianesi, Miriam Bianca, Paola Di Franco, Simone Sardina, Davide Stefano Veschi, Veronica Signore, Michele Beyes, Sven Fagnocchi, Luca Fiori, Micol Eleonora Bongiorno, Maria Rita Lo Iacono, Melania Pillitteri, Irene Ganduscio, Gloria Gulotta, Gaspare Medema, Jan Paul Zippo, Alessio Todaro, Matilde De Maria, Ruggero Stassi, Giorgio Gut Colon OBJECTIVE: Cancer stem cells are responsible for tumour spreading and relapse. Human epidermal growth factor receptor 2 (HER2) expression is a negative prognostic factor in colorectal cancer (CRC) and a potential target in tumours carrying the gene amplification. Our aim was to define the expression of HER2 in colorectal cancer stem cells (CR-CSCs) and its possible role as therapeutic target in CRC resistant to anti- epidermal growth factor receptor (EGFR) therapy. DESIGN: A collection of primary sphere cell cultures obtained from 60 CRC specimens was used to generate CR-CSC mouse avatars to preclinically validate therapeutic options. We also made use of the ChIP-seq analysis for transcriptional evaluation of HER2 activation and global RNA-seq to identify the mechanisms underlying therapy resistance. RESULTS: Here we show that in CD44v6-positive CR-CSCs, high HER2 expression levels are associated with an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which promotes the acetylation at the regulatory elements of the Erbb2 gene. HER2 targeting in combination with phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase kinase (MEK) inhibitors induces CR-CSC death and regression of tumour xenografts, including those carrying Kras and Pik3ca mutation. Requirement for the triple targeting is due to the presence of cancer-associated fibroblasts, which release cytokines able to confer CR-CSC resistance to PI3K/AKT inhibitors. In contrast, targeting of PI3K/AKT as monotherapy is sufficient to kill liver-disseminating CR-CSCs in a model of adjuvant therapy. CONCLUSIONS: While PI3K targeting kills liver-colonising CR-CSCs, the concomitant inhibition of PI3K, HER2 and MEK is required to induce regression of tumours resistant to anti-EGFR therapies. These data may provide a rationale for designing clinical trials in the adjuvant and metastatic setting. BMJ Publishing Group 2022-01 2021-01-12 /pmc/articles/PMC8666826/ /pubmed/33436496 http://dx.doi.org/10.1136/gutjnl-2020-323553 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Colon Mangiapane, Laura Rosa Nicotra, Annalisa Turdo, Alice Gaggianesi, Miriam Bianca, Paola Di Franco, Simone Sardina, Davide Stefano Veschi, Veronica Signore, Michele Beyes, Sven Fagnocchi, Luca Fiori, Micol Eleonora Bongiorno, Maria Rita Lo Iacono, Melania Pillitteri, Irene Ganduscio, Gloria Gulotta, Gaspare Medema, Jan Paul Zippo, Alessio Todaro, Matilde De Maria, Ruggero Stassi, Giorgio PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells |
title | PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells |
title_full | PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells |
title_fullStr | PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells |
title_full_unstemmed | PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells |
title_short | PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells |
title_sort | pi3k-driven her2 expression is a potential therapeutic target in colorectal cancer stem cells |
topic | Colon |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8666826/ https://www.ncbi.nlm.nih.gov/pubmed/33436496 http://dx.doi.org/10.1136/gutjnl-2020-323553 |
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