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Mangiapane LR, Nicotra A, Turdo A, et al. PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells. Gut. 2021;71(1):119-128doi: 10.1136/gutjnl-2020-323553.
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. (2022). PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells. Gut, 71(1), 119-128. https://doi.org/10.1136/gutjnl-2020-323553
Mangiapane, Laura Rosa, et al. "PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells." Gut vol. 71,1 (2022): 119-128. doi: https://doi.org/10.1136/gutjnl-2020-323553
Mangiapane LR, Nicotra A, Turdo A, Gaggianesi M, Bianca P, Di Franco S, Sardina DS, Veschi V, Signore M, Beyes S, Fagnocchi L, Fiori ME, Bongiorno MR, Lo Iacono M, Pillitteri I, Ganduscio G, Gulotta G, Medema JP, Zippo A, Todaro M, De Maria R, Stassi G. PI3K-driven HER2 expression is a potential therapeutic target in colorectal cancer stem cells. Gut. 2022 Jan;71(1):119-128. doi: 10.1136/gutjnl-2020-323553. Epub 2021 Jan 12. PMID: 33436496.
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Gut. 2022 Jan;71(1):119-128. doi: 10.1136/gutjnl-2020-323553. Epub 2021 Jan 12.

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

Gut

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

Affiliations

  1. Department of Surgical, Oncological and Stomatological Sciences, Università degli Studi di Palermo, Palermo, Italy.
  2. Department of Health Promotion Sciences, Internal Medicine and Medical Specialties, Università degli Studi di Palermo, Palermo, Italy.
  3. Core Facilities, Istituto Superiore di Sanità, Roma, Italy.
  4. Department of Cellular, Computational, and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  5. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanita, Roma, Italy.
  6. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, University of Amsterdam, Amsterdam, Noord-Holland, The Netherlands.
  7. Oncode Institute, University of Amsterdam, Amsterdam, Noord-Holland, The Netherlands.
  8. Institute of General Pathology, Universita Cattolica del Sacro Cuore Facolta di Medicina e Chirurgia, Roma, Italy [email protected] [email protected].
  9. Policlinico A Gemelli, Roma, Lazio, Italy.
  10. Department of Surgical, Oncological and Stomatological Sciences, Università degli Studi di Palermo, Palermo, Italy [email protected] [email protected].

PMID: 33436496 DOI: 10.1136/gutjnl-2020-323553

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

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.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Keywords: antibody targeted therapy; colorectal cancer; drug resistance; stem cells

Conflict of interest statement

Competing interests: None declared.

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