Alexandre Bozec1, Nathalie Ebran2, Nina Radosevic-Robin3,4, Emmanuel Chamorey5, Hedi Ben Yahia2, Serge Marcie6, Mathieu Gautier6, Frédérique Penault-Llorca3,4, Gérard Milano2. 1. University Institute of the Face and Neck, Nice cedex, France. 2. Department of Oncopharmacology, Antoine Lacassagne Comprehensive Cancer Centre, Nice cedex, France. 3. Department of Pathology, Jean Perrin Comprehensive Cancer Centre, Clermont-Ferrand, France. 4. ERTICa Research Group, University of Auvergne, Clermont-Ferrand, France. 5. Department of Clinical Research, Innovation and Statistics (DRIS), Antoine Lacassagne Comprehensive Cancer Centre, Nice cedex, France. 6. Department of Physics, Antoine Lacassagne Comprehensive Cancer Centre, Nice cedex, France.
Abstract
BACKGROUND: The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). METHODS: We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the human PIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice. RESULTS: Compared with control, the BKM120-cetuximab and the BKM120-cetuximab-RT combinations led to the highest tumor inhibition (p < .001). The highest inhibitory effect of treatments on cell proliferation, mitogen-activated protein kinase (MAPK) and PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways were found with the BKM120-cetuximab association. The association of BKM120 and cetuximab with RT inhibited RT-induced activation of the MAPK pathway. CONCLUSION: These results can serve as a preclinical rationale for innovative treatments combining PI3K inhibition with anti-EGFR therapies and irradiation in patients with HNSCC.
BACKGROUND: The purpose of this study was to investigate the effects of combining the phosphotidylinositol-3-kinase (PI3K) inhibitor buparlisib (BKM)120 with the anti-epidermal growth factor receptor (EGFR) agent cetuximab and radiotherapy (RT) on an orthotopic model of head and neck squamous cell carcinoma (HNSCC). METHODS: We evaluated the antitumor efficacy of BKM120, cetuximab, and RT, administered alone or in combination, using the humanPIK3CA-mutated HNSCC cell line, CAL33, injected into the floor of the mouth of nude mice. RESULTS: Compared with control, the BKM120-cetuximab and the BKM120-cetuximab-RT combinations led to the highest tumor inhibition (p < .001). The highest inhibitory effect of treatments on cell proliferation, mitogen-activated protein kinase (MAPK) and PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways were found with the BKM120-cetuximab association. The association of BKM120 and cetuximab with RT inhibited RT-induced activation of the MAPK pathway. CONCLUSION: These results can serve as a preclinical rationale for innovative treatments combining PI3K inhibition with anti-EGFR therapies and irradiation in patients with HNSCC.