Jean-Baptiste Guy1,2,3, Sophie Espenel4,5,6, Claire Rodriguez-Lafrasse4,5,7, Nicolas Magné5,6, Safa Louati4,5,6, Arnaud Gauthier4,5,7, Max-Adrien Garcia8, Nicolas Vial6, Céline Malésys4,5, Dominique Ardail4,5,7, Gersende Alphonse5,7, Anne-Sophie Wozny4,5,7. 1. Faculté de Médecine-Lyon-Sud, Université Lyon 1, 69921, Oullins, France. jeanbaguy@gmail.com. 2. Laboratoire de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud, CNRS UMR 5822 IP2I, 165 Chemin du Grand Revoyet, BP 12, 69921, Oullins Cedex, France. jeanbaguy@gmail.com. 3. Département de Radiothérapie, Institut de Cancérologie de La Loire, Lucien Neuwirth, 42270, St Priest en Jarez, France. jeanbaguy@gmail.com. 4. Faculté de Médecine-Lyon-Sud, Université Lyon 1, 69921, Oullins, France. 5. Laboratoire de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud, CNRS UMR 5822 IP2I, 165 Chemin du Grand Revoyet, BP 12, 69921, Oullins Cedex, France. 6. Département de Radiothérapie, Institut de Cancérologie de La Loire, Lucien Neuwirth, 42270, St Priest en Jarez, France. 7. Hospices Civils de Lyon, 69229, Lyon, France. 8. Département de Santé Publique, Institut de Cancérologie de La Loire, Lucien Neuwirth, 42270, St Priest en Jarez, France.
Abstract
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.
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.
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