Abstract 417: Targeting aurora kinase b overcomes acquired resistance to met-tyrosine kinase inhibitor in met-amplified lung cancer

Abstract

Abstract Mesenchymal-epithelial transition factor receptor (MET) mediated signaling emerged as an important clinical target for the treatment of many cancer types including non-small cell lung cancer. MET amplification is prevalent in 2%~4% of primary lung cancer and 15%~50% of EGFR-mutated lung cancer resistant to EGFR inhibitors. Currently, MET-targeting drugs have been actively investigated in these MET-amplified lung cancers. However, the acquired resistance mechanism for MET-targeted therapy remains unknown. Our study aims to provide effective treatment for overcoming MET-TKI-acquired resistance in MET-amplified non-small cell lung cancer. To discover the resistance mechanism, we established the resistant cell line (PR-S2) by chronic exposure of MET-amplified lung cancer cells (H1993) to MET kinase inhibitor, PHA665752. Through high-throughput screening of a custom library of 276 compounds, we found that Aurora kinase B (AURKB) inhibitor, barasertib was more sensitive to the PR-S2 cells than H1993 cells. AURKB inhibition by barasertib induced apoptotic cell death with G2/M arrest and polyploid cell formation in the PR-S2 cells. The expression of p-AURKB was increased with no change in the expression of p-histone H3, a major product of AURKB in the PR-S2 cells. AURKB knockdown using multiple siRNA sequences increases the sensitivity to PHA665752 in the PR-S2 cells. In mRNA sequencing data analysis, we found the expression of signal transducer and activator of transcription 3 (STAT3) was elevated in the PR-S2 cells compared to the H1993 cells. We confirmed increased STAT3 expression in both protein and mRNA levels in the PR-S2 cells. p-STAT3 expression was decreased after barasertib treatment in the PR-S2 cells. However, in the immunoprecipitation assay, there was no direct interaction between AURKB and STAT3. To know the target of STAT3, we checked the mRNA expression of downstream genes of STAT3. The expression of BCL-2, one of the downstream targets of STAT3 and the central apoptosis regulator, was highly upregulated in the resistant cells. The siRNA-mediated knockdown of STAT3 expression decreased BCL2 expression in the PR-S2 cells, whereas not in the H1993 cells. Furthermore, we investigated apoptosis-related gene expressions and found that the BH3-only proapoptotic member of the BCL-2 protein family, BIM was significantly decreased in the PR-S2 cells. AURKB inhibition induced BIMEL accumulation and reduced p-BIM expression. Collectively, our study suggests that AURKB activation induces resistance to MET-TKI through anti-apoptosis mechanism with upregulation of STAT3/BCL2 axis in MET-amplified lung cancer cells. Citation Format: Yura Choi, Mihwa Hwang, Sunshin Kim, Jae J. Song, Youngjoo Lee. Targeting aurora kinase b overcomes acquired resistance to met-tyrosine kinase inhibitor in met-amplified lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 417.