Abstract 4756: Activation of AURKA contributes to TKI resistance in EGFR-mutant non-small lung cancer

Abstract

Abstract The epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used to treat EGFR-mutant non-small cell lung cancer (NSCLC) in clinics. Several generations of TKI were invented to overcome the unfavorable response and acquired resistance after long-term usage of EGFR TKI. Several mechanisms of acquired resistance have been reported. The well-studied resistant mechanism results from EGFR secondary mutations including T790M and C797S, which are involved in the resistance to first and third generation TKI, respectively. Other mechanisms aside from secondary mutation on EGFR including Her2 and MET amplification or epithelial mesenchymal transition (EMT) also distribute to TKI resistance. However, the resistant mechanisms which are independent to these alterations have not been completely identified yet. Here, we generated resistant cells selected by three different generations of TKI and analyzed their gene expression profiles. We discovered that many signal pathways, especially involved in cell cycle regulation, are commonly upregulated in three TKI-resistant cell lines. Aurora kinase A (AURKA) was the upstream kinase of those pathways; however, neither RNA level nor protein level of AURKA was significant changed. Interestingly, we found that phosphorylation of Aurora A at Thr288 in its catalytic domain is higher in TKI resistant cells. This reveals the possibilities that AURKA activation plays a role in the occurrence of TKI-resistance and that TKI-resistant NSCLC patients have a better response rate to AURKA inhibitor treatments. Citation Format: Meng-Hsuan Lee, Shiao-Ya Hong, Yu-Rung Kao, Cheng-Wen Wu. Activation of AURKA contributes to TKI resistance in EGFR-mutant non-small lung cancer [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 4756.