TY - JOUR
T1 - PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells
AU - Mangiapane, Laura Rosa
AU - Nicotra, Annalisa
AU - Turdo, Alice
AU - Gaggianesi, Miriam
AU - Bianca, Paola
AU - di Franco, Simone
AU - Sardina, Davide Stefano
AU - Veschi, Veronica
AU - Signore, Michele
AU - Beyes, Sven
AU - Fagnocchi, Luca
AU - Fiori, Micol Eleonora
AU - Bongiorno, Maria Rita
AU - Lo Iacono, Melania
AU - Pillitteri, Irene
AU - Ganduscio, Gloria
AU - Gulotta, Gaspare
AU - Medema, Jan Paul
AU - Zippo, Alessio
AU - Todaro, Matilde
AU - de Maria, Ruggero
AU - Stassi, Giorgio
N1 - Funding Information: Funding This work was supported by AIRC 5x1000 (9979) to GS and RDM, AIRC IG (22911) to AZ, RF2018-12367044 to MT and RDM, AIRC IG (21445) and PRIN (2017WNKSLR) to GS. Funding Information: Acknowledgements We thank Francesco Calò for graphic image editing and Alice Alferi for technical assistance. LRM is a student of the Molecular and Clinical Medicine PhD Program. AT and VV are research fellows funded by European Union-FESR FSE, PON Ricerca e Innovazione 2014–2020 (AIM line 1). Publisher Copyright: © 2022, BMJ Publishing Group Ltd and British Society of Gastroenterology. All rights reserved.
PY - 2022/1/1
Y1 - 2022/1/1
N2 - 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. 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. 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 carryingKrasandPik3camutation. 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. 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.
AB - 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. 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. 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 carryingKrasandPik3camutation. 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. 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.
KW - antibody targeted therapy
KW - colorectal cancer
KW - drug resistance
KW - stem cells
UR - http://www.scopus.com/inward/record.url?scp=85099337829&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/gutjnl-2020-323553
DO - https://doi.org/10.1136/gutjnl-2020-323553
M3 - Article
C2 - 33436496
SN - 0017-5749
VL - 71
SP - 119
EP - 128
JO - Gut
JF - Gut
IS - 1
ER -