Combining radiation to EGFR and Bcl-2 blockade: a new approach to target cancer stem cells in head and neck squamous cell carcinoma

Purpose The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor, partly due to the presence of resistant cancer stem cells (CSCs) which are responsible of recurrences. CSCs have low EGFR expression and, conversely, overexpress the anti-apoptotic Bcl-2 protein, which is inv...

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Published in:Journal of cancer research and clinical oncology 2021-07, Vol.147 (7), p.1905-1916
Main Authors: Guy, Jean-Baptiste, Espenel, Sophie, Louati, Safa, Gauthier, Arnaud, Garcia, Max-Adrien, Vial, Nicolas, Malésys, Céline, Ardail, Dominique, Alphonse, Gersende, Wozny, Anne-Sophie, Rodriguez-Lafrasse, Claire, Magné, Nicolas
Format: Article
Language:English
Subjects:
Apoptosis
Bcl-2 protein
Cancer
Cancer Research
Cell growth
Cell migration
Cell proliferation
Clinical trials
Epidermal growth factor receptors
Head & neck cancer
Hematology
Internal Medicine
Life Sciences
Life span
Medicine
Medicine & Public Health
Monoclonal antibodies
Oncology
Original Article – Cancer Research
Radiation
Squamous cell carcinoma
Stem cell transplantation
Stem cells
Targeted cancer therapy
Tumors
Xenografts
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Summary:Purpose The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor, partly due to the presence of resistant cancer stem cells (CSCs) which are responsible of recurrences. CSCs have low EGFR expression and, conversely, overexpress the anti-apoptotic Bcl-2 protein, which is involved in resistance to apoptosis and the invasion/migration capacities of tumour cells. Methods The combination therapy of ABT-199, a Bcl-2 inhibitor, cetuximab an EGFR inhibitor, and radiation using an HNSCC model (SQ20B cell line) and its corresponding CSC subpopulation were evaluated in vitro (2D/3D cell proliferation; invasion/migration and apoptosis using videomicroscopy) and in vivo. Results Cetuximab strongly inhibited 2D and 3D cell proliferation, as well as invasion/migration, only in non-CSC-SQ20B cells, whereas ABT-199 selectively inhibited these mechanisms in SQ20B/CSCs. The combination of irradiation + cetuximab + ABT-199 increased the inhibition of the 2D and 3D cell proliferation, invasion/migration, and resistance to apoptosis in both cell sub-populations. In addition, in a nude mouse model with heterotopic tumour xenograft, a treatment combining cetuximab + ABT-199 with fractional irradiation strongly delayed the tumour growth and increased in vivo lifespan without side effects. Conclusion Based on the present results, this triple combination therapy may represent a new opportunity for testing in clinical trials, particularly in locally advanced HNSCC.
ISSN:0171-5216
1432-1335
DOI:10.1007/s00432-021-03593-8