1. PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
- Author
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Paola Bianca, Melania Lo Iacono, Laura Rosa Mangiapane, Micol E. Fiori, Maria Rita Bongiorno, Matilde Todaro, Luca Fagnocchi, Sven Beyes, Michele Signore, Veronica Veschi, Miriam Gaggianesi, Jan Paul Medema, Gaspare Gulotta, Irene Pillitteri, Annalisa Nicotra, Alice Turdo, Simone Di Franco, Ruggero De Maria, Gloria Ganduscio, Davide Stefano Sardina, Alessio Zippo, Giorgio Stassi, 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., Center of Experimental and Molecular Medicine, Radiotherapy, and CCA - Cancer biology and immunology
- Subjects
0301 basic medicine ,Receptor, ErbB-2 ,Colorectal cancer ,Cetuximab ,colorectal cancer ,medicine.disease_cause ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Settore MED/04 - PATOLOGIA GENERALE ,Cancer stem cell ,stem cells ,Tumor Cells, Cultured ,medicine ,Adjuvant therapy ,Animals ,Humans ,Epidermal growth factor receptor ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,Mitogen-Activated Protein Kinase Kinases ,drug resistance ,biology ,business.industry ,Gastroenterology ,Trastuzumab ,medicine.disease ,antibody targeted therapy ,030104 developmental biology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,biology.protein ,KRAS ,Phosphatidylinositol 3-Kinase ,Stem cell ,Colorectal Neoplasms ,business - Abstract
ObjectiveCancer 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.DesignA 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.ResultsHere 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.ConclusionsWhile 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.
- Published
- 2021