Abstract 1282: Combination of PI3K targeting with cetuximab and irradiation: a preclinical study on an orthotopic xenograft model of head and neck cancer

Abstract

Abstract The PI3-kinase (PI3K)/AKT/mTOR signaling pathway is of particular interest in head and neck squamous cell carcinoma (HNSCC). Its activation has been identified as an important mechanism implicated in tumor progression and resistance to epidermal growth factor receptor (EGFR) inhibitors. The anti-EGFR monoclonal antibody cetuximab (Cet), radiotherapy (RT) and their combination are widely used in the therapeutic management of patients with HNSCC. Inhibition of the PI3K/AKT/mTOR signaling pathway has been shown to potentialize the effects of anti-EGFR agents and RT. We conducted a preliminary in vitro study demonstrating synergistic effects of Cet followed by the PI3K inhibitor BKM120 (Buparlisib) in both PI3KCA wild-type and mutated cells. The aim of the present study was to investigate the effects of combining BKM120 with Cet and RT on an orthotopic xenograft model of HNSCC. In the present study we have used an orthotopic (floor of the mouth) model of human HNSCC to measure the effects of a treatment including BKM120 (40 mg/kg, 5 days/week, p.o.), Cet (2,5 mg/kg/day, 1 day/week, i.p.) and RT (6 Gy/dose, 3 days/week), administered alone or in combination. Investigations were performed using the human PI3KCA-mutated (H1047R) HNSCC cell line, CAL33, injected into the mouth floor of nude mice. The tumor growth was followed by IVIS imagery on days 3, 7 and 12 and tumor size was checked with a caliper ruler on day 13 after animal euthanasia. As compared with the control, the BKM120-Cet and the BKM120-Cet-RT combinations led to the highest tumor inhibition and induced almost complete tumor growth arrest (p < 0.001). The addition of BKM120 and Cet to RT significantly enhanced the impact of RT alone on tumor growth (p < 0.001). The highest inhibitory effects of treatments on cell proliferation (Ki67 labelling), MAPK (pERK labelling) and PI3K/AKT/mTOR (pS6R labelling) signaling pathways were found with the BKM120-Cet association. RT alone (p = 0.10) tended to activate the MAPK pathway but the association of BKM120 and Cet to RT inhibited the RT-induced activation of the MAPK pathway (p = 0.03). In conclusion, in this orthotopic HNSCC model, the combination of BKM120 with Cet and RT produced synergistic effects on tumor growth. These results could serve as a strong preclinical basis for innovative treatments combining PI3K inhibition with anti-EGFR therapies and RT in patients with HNSCC. Citation Format: Gérard Milano, Alexandre Bozec, Nathalie Ebran. Combination of PI3K targeting with cetuximab and irradiation: a preclinical study on an orthotopic xenograft model of head and neck cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1282.