Abstract 298: Identification and evaluation of novel drug combinations with aurora kinase inhibitor CCT137690 for enhanced efficacy in 2D monolayer and 3D spheroid model of oral cancer cells

Abstract

Abstract Background: Oral cancer is the most prevalent subtype of head and neck cancers with a high incidence among men in South-Central Asia and Central and Eastern Europe. The mortality rate is disproportionately high in developing countries, presumably due to late diagnosis and limited access to quality treatment. Despite the advances in the understanding of the molecular basis and treatment of oral cancer during the last decade, the survival rates remain poor for patients with the advanced metastatic disease. Deregulated expression of Aurora family of mitotic kinases has also been associated with pathogenesis and poor prognosis in many cancers including oral cancers. Here we have evaluated the efficacy of pan-Aurora inhibitor, CCT137690, in oral cancer cell lines and identified that it synergizes with EGFR and PI-3 kinase inhibitors in 2D monolayer and 3D spheroid models. Methods: Inhibition of aurora kinases followed by induction of apoptosis in control and CCT137690 treated samples were analyzed through western blotting and immunofluorescence. We assessed proliferation of oral cancer cells through SRB assay, while cell cycle profile following inhibitor treatment was analyzed through flow cytometry. We also synthesized polyethylene glycol based Nanocapsules (P-NCps) containing combinations of CCT137690 with GDC-0941 (CG-L-P-NCps) or ZD1839 (CGe-L-P-NCps) and compared their efficacy with free drug combinations through proliferation assay in 2D monolayer and 3D spheroid model of oral cancer cells. Results: CCT137690 treatment inhibited proliferation and induced apoptosis in both types of oral cancer cell lines (ORL-48 and ORL-115). Such inhibition was accompanied by significant morphological changes in cells such as aberrant mitotic spindle formation, endoreduplication and increased cell size. Combining CCT137690 with inhibitors of EGFR (ZD1839) or PI3K (GDC-0941) synergistically reduced proliferation and increased apoptosis induction in the oral cancer cells. Furthermore, Nanocapsules harboring these drug combinations also showed a comparable inhibitory effect in 2D monolayer and 3D spheroid model of oral cancer cells. Conclusion: Our results suggest that the combination of CCT137690 with ZD1839 or GDC-0941 can be further evaluated for the treatment of oral cancer. Moreover, these combinations can be delivered through nanocapsules to confer additional advantages of reduced cytotoxicity and sustained release for better therapeutic index and efficacy. Citation Format: Muhammad Furqan, Zainab Ashfaq, Apsra Nasir, Zille Huma, Rahim Ullah, Maheen Iqbal, Irshad Hussain, Amir Faisal. Identification and evaluation of novel drug combinations with aurora kinase inhibitor CCT137690 for enhanced efficacy in 2D monolayer and 3D spheroid model of oral cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 298.