Abstract 2928: AZD6244 inhibits cisplatin induced ERK1/2 activation and potentiates its cytotoxic effects in NSCLC preclinical models

Abstract

Abstract Introduction; Lung cancer is still the leading cause of cancer death worldwide, indicating that there are urgent needs for elucidating the mechanisms of resistance and developments of strategies to overcome it. Cisplatin is still one of the most commonly used drugs for the treatment of advanced lung cancer and, however, the underlying mechanism of activation of MAPK/ERK1/2 after cisplatin administration is still complex and elusive. It is considered one of the main mechanisms mediating resistance to cisplatin based doublet chemotherapy. In this study we aimed to evaluate the effectiveness of combination of MAPK inhibitor, AZD6244, with cisplatin in NSCLC models. Materials and Methods; NSCLC cells harbouring oncogenic RAS mutation, NCI-H1299, -H2009, -H460, and A549 cells, and LSL K-Ras G12D mouse model was used. Protein expression was evaluated by immunoblotting and cytotoxicity was measured by FACS followed by annexin-V and PI staining. LSL Kras G12D mouse were inhaled 5X 107 PFU AdCre virus at 8 weeks after birth and, in 24 weeks after inhalation, were taken microCT, randomized into 4 groups, and then treated with AZD6244 (25mg/kg bid by oral gavage) and/or cisplatin (5 mg/kg weekly) for two weeks. Results; There was a dose dependent increase of pERK1/2, which is most prominent at 24 hr after cisplatin treatment. Expression of proapoptotic protein, BIM, was decreased whereas that of antiapoptotic proteins, BCL-2 and MCL-1, was increased with cisplatin treatment. Treatment of AZD6244 prevented phosphorylation mediated degradation of BIM after cisplatin treatment. AZD6244 itself did not show cytotoxic effects up to 10 uM whereas combination of 1 uM of AZD6244 potentiates cytotoxic effects of cisplatin. Combined treatment of AZD6244 with cisplatin showed significant tumor reduction in 2 weeks in LSL K-ras G12D mouse model when compared those treated with single agents or vehicle. Conclusion; Combination of AZD6244 with cisplatin potentiates cytotoxic effects and anti-tumor activities in NSCLC preclinical models. These findings suggest that clinical trials using combination with AZD6244 and cisplatin may be beneficial in advanced NSCLC patients. Citation Format: Eun Young Kim, Arum Kim, Min Kwang Byun, Se Kyu Kim, Hyung Jung Kim, Joon Chang, Chul Min Ahn, Yoon Soo Chang. AZD6244 inhibits cisplatin induced ERK1/2 activation and potentiates its cytotoxic effects in NSCLC preclinical models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2928. doi:10.1158/1538-7445.AM2014-2928