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. 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. 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 carryingKrasandPik3camutation. 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. 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.

PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells / Mangiapane, L. R.; Nicotra, A.; Turdo, A.; Gaggianesi, M.; Bianca, P.; Di Franco, S.; Sardina, D. S.; Veschi, V.; Signore, M.; Beyes, S.; Fagnocchi, L.; Fiori, M. E.; Bongiorno, M. R.; Lo Iacono, M.; Pillitteri, I.; Ganduscio, G.; Gulotta, G.; Medema, J. P.; Zippo, A.; Todaro, M.; De Maria, R.; Stassi, G.. - In: GUT. - ISSN 0017-5749. - 71:1(2022), pp. 119-128. [10.1136/gutjnl-2020-323553]

PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells

Beyes S.;Fagnocchi L.;Lo Iacono M.;Zippo A.;Todaro M.;
2022

Abstract

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. 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. 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 carryingKrasandPik3camutation. 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. 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.
GUT
1
Mangiapane, L. R.; Nicotra, A.; Turdo, A.; Gaggianesi, M.; Bianca, P.; Di Franco, S.; Sardina, D. S.; Veschi, V.; Signore, M.; Beyes, S.; Fagnocchi, L.; Fiori, M. E.; Bongiorno, M. R.; Lo Iacono, M.; Pillitteri, I.; Ganduscio, G.; Gulotta, G.; Medema, J. P.; Zippo, A.; Todaro, M.; De Maria, R.; Stassi, G.
PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells / Mangiapane, L. R.; Nicotra, A.; Turdo, A.; Gaggianesi, M.; Bianca, P.; Di Franco, S.; Sardina, D. S.; Veschi, V.; Signore, M.; Beyes, S.; Fagnocchi, L.; Fiori, M. E.; Bongiorno, M. R.; Lo Iacono, M.; Pillitteri, I.; Ganduscio, G.; Gulotta, G.; Medema, J. P.; Zippo, A.; Todaro, M.; De Maria, R.; Stassi, G.. - In: GUT. - ISSN 0017-5749. - 71:1(2022), pp. 119-128. [10.1136/gutjnl-2020-323553]
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