Abstract 4390: Aurora kinases: potential therapeutic targets in K-Ras-induced lung cancer.

Abstract

Abstract K-Ras-induced lung cancer is a very common disease, for which there are currently no effective therapies. Intense efforts are underway to identify K-Ras targets that play a crucial role in oncogenesis. We have previously shown that K-Ras-induced lung tumorigenesis is potentiated by the transcription factor NF-κB; and others have shown that Aurora kinases, not only play a significant role in tumorigenesis, but also can activate NF-κB. Therefore, we hypothesized that Aurora A and/or Aurora B are important K-Ras targets in lung cancer. In order to test this hypothesis, we first determined whether oncogenic K-Ras induces Aurora kinase expression. For that purpose, we used three different cell-based models: (1) an immortalized primary lung epithelial cell line and its isogenic K-Ras-transformed counterpart, (2) H1703 lung cancer cell line engineered to express oncogenic K-Ras inducibly, and (3) K-Ras positive lung cancer cell lines H358 and A549 stably expressing inducible shRNAs targeting K-Ras. In all cases, K-Ras expression positively correlated with Aurora A and Aurora B expression. In order to validate Aurora A an B as therapeutically relevant K-Ras targets in lung cancer, we used genetic and/or pharmacological approaches in the abovementioned cells to inactivate Aurora A or B. Inducible shRNA-mediated knockdown of Aurora A or B, as well as treatment with a dual Aurora A and B inhibitor (AI II), decreased growth, viability and migration of K-Ras positive H358 and A549 cell lines. Interestingly, in our primary isogenic model and in our H1703 K-Ras-inducible cell line, AI II reduced viability and induced apoptosis in an oncogenic K-Ras-dependent manner. This suggests that Aurora kinase inhibition therapy can specifically target K-Ras transformed cells. In conclusion, our results support our hypothesis that Aurora kinases are important K-Ras targets in lung cancer and suggest Aurora kinase inhibition as a novel approach for K-Ras-induced lung cancer therapy. Citation Format: Edmilson O. dos Santos, Mateus N. Aoki, Daniela S. Bassères. Aurora kinases: potential therapeutic targets in K-Ras-induced lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4390. doi:10.1158/1538-7445.AM2013-4390