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

Melania Lo Iacono, Gloria Ganduscio, Giorgio Stassi, Gaspare Gulotta, Miriam Gaggianesi, Laura Rosa Mangiapane, Matilde Todaro, Simone Di Franco, Veronica Veschi, Maria Rita Bongiorno, Alice Turdo, Annalisa Nicotra, Luca Fagnocchi, Sven Beyes, Alessio Zippo, Michele Signore, Jan Paul Medema, Micol Eleonora Fiori, Ruggero De Maria

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Abstract

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.
Original languageEnglish
Pages (from-to)gutjnl-2020-323553-
Number of pages10
JournalGut
Publication statusPublished - 2021

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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