PT  - JOURNAL ARTICLE
AU  - Laura Rosa Mangiapane
AU  - Annalisa Nicotra
AU  - Alice Turdo
AU  - Miriam Gaggianesi
AU  - Paola Bianca
AU  - Simone Di Franco
AU  - Davide Stefano Sardina
AU  - Veronica Veschi
AU  - Michele Signore
AU  - Sven Beyes
AU  - Luca Fagnocchi
AU  - Micol Eleonora Fiori
AU  - Maria Rita Bongiorno
AU  - Melania Lo Iacono
AU  - Irene Pillitteri
AU  - Gloria Ganduscio
AU  - Gaspare Gulotta
AU  - Jan Paul Medema
AU  - Alessio Zippo
AU  - Matilde Todaro
AU  - Ruggero De Maria
AU  - Giorgio Stassi
TI  - PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
AID  - 10.1136/gutjnl-2020-323553
DP  - 2022 Jan 01
TA  - Gut
PG  - 119--128
VI  - 71
IP  - 1
4099  - http://gut.bmj.com/content/71/1/119.short
4100  - http://gut.bmj.com/content/71/1/119.full
SO  - Gut2022 Jan 01; 71
AB  - 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.Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. The data that support the findings of this study are available from the corresponding author (GS) upon reasonable request. RNA sequencing data of CR-CSphCs have been deposited in a public, open access GEO repository, under accession number GSE162104 (link to data: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162104).