RT Journal Article
SR Electronic
T1 PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2020-323553
DO 10.1136/gutjnl-2020-323553
A1 Laura Rosa Mangiapane
A1 Annalisa Nicotra
A1 Alice Turdo
A1 Miriam Gaggianesi
A1 Paola Bianca
A1 Simone Di Franco
A1 Davide Stefano Sardina
A1 Veronica Veschi
A1 Michele Signore
A1 Sven Beyes
A1 Luca Fagnocchi
A1 Micol Eleonora Fiori
A1 Maria Rita Bongiorno
A1 Melania Lo Iacono
A1 Irene Pillitteri
A1 Gloria Ganduscio
A1 Gaspare Gulotta
A1 Jan Paul Medema
A1 Alessio Zippo
A1 Matilde Todaro
A1 Ruggero De Maria
A1 Giorgio Stassi
YR 2021
UL http://gut.bmj.com/content/early/2021/02/21/gutjnl-2020-323553.abstract
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.