Abstract
Abstract Background:Erlotinib, an EGFR selective reversible inhibitor, improved response of patients diagnosed with non-small cell lung cancer (NSCLC) with 70% of patients showing significant tumor regression upon treatment. Unfortunately,most patients eventually relapse due to development of resistance. Our research goal is to quantify the effects of combination treatment of erlotinib with a glycyrrhetinic acid analogs and to improve the oral bioavailability of this treatment using self nano-emulsifying drug delivery systems. Methods: NSCLC cell lines HCC827, HCC827 (4µM erlotinib resistant), HCC827 Cl4 (second site EGFR mutated), HCC827BEAS2B, and H1975 (4µMerlotinib resistant) were treated in combination with CDODA-Me, CF3CDODA-Me and Erlotinib. The cell viability assays were performed and combination index (CI) values were calculated by isobolographic analysis. Self nano-emulsifying drug delivery systems (SNEDDs) were formulated and characterized through in vitro and in vivo studies. Results: CF3CDODA and improved efficacy for erlotinib in all cell lines with IC50 values of 6.0µM, 7.8µM, 4.6µM and 4.2±1.56µM for HCC827(RESISTANT), H1975(RESISTANT), HCC827CL4 and HCC827 respectively compared to IC50values of erlotinib alone (25µM, 21µM, 23µM, and 8µM). This was superior when compared to IC50 values of CDODA-Me combination treatment (6.66µM, 7.32µM, 12.06µM, and 5.45µM respectively). Combination treatment showed strong synergism with a constant concentration of 0.5µM CF3CDODA and CI values of 0.461, 0.548, 0.389, 0.550 for HCC827 4µM, H1975µM, HCC827CL4, and HCC827 respectively and antagonism in HCC827BEAS2B (1.508) cells. This is comparable to the synergism observed at a minimum concentration of 2µM CDODA-Me with CI values of 0.337, 0.67, 0.64, and 0.657 respectively and antagonism CI of 1.175 for HCC827BEAS2B. CF3CDODA Combination therapy showed a 2.5-fold decrease in colony formation in resistant cells making them comparable to wild type. This was comparable to CDODA-Me combination treatment with a 1.46-fold decrease in colony formation. Both combination treatments showed little effect on HCC827BEAS2B. Western Blot analysis showed decrease MET expression and decreased apoptosis inhibiting markers BCL2 and Survivin. SNEDD formulations increased maximum drug plasma concentrations for Erlotinib (281ng/ml to 442ng/ml) and circulating time as well (12hrs - 21hrs). Conclusions: Based on the results of these studies, CDODA-Me and CF3CDODA have shown to overcome erlotinib resistance in non-small cell lung cancer and when combining these treatments with the use of SNEDDS, they have shown to be a promising treatment regimen. Citation Format: Ebony Nottingham, Vasanth Sekar, Arindam Mondal, Mandip Sachdeva. The use of self nano-emulsifying drug delivery systems to improve bioavailability of combination therapy and overcome erlotinib resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2039. doi:10.1158/1538-7445.AM2017-2039
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