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PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
- Source :
- Gut, 71(1), 119-128. BMJ Publishing Group
- Publication Year :
- 2021
- Publisher :
- BMJ Publishing Group, 2021.
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00175749
- Database :
- OpenAIRE
- Journal :
- Gut, 71(1), 119-128. BMJ Publishing Group
- Accession number :
- edsair.doi.dedup.....fac3cf44e52a8889d307bbba5462dd05