Abstract 4116: Acquired lapatinib resistant induces EMT-phenotype in breast cancer cells via Src and RUNX3

Abstract

Abstract Background: Lapatinib is an effective EGFR and HER2 targeting small molecular tyrosine kinase inhibitor which is widely used for HER2 positive breast cancer patients. However, patients eventually acquire resistance, limiting its long-term use. Overexpression of heregulin, a HER3 ligand, acquired stemness were mechanism that confers resistance to the anti-HER2 lapatinib. However, still, unknown mechanisms of developing lapatinib resistant remain as a question to solve. Thus, we tried to find out there is a novel mechanism which related to lapatinib resistant, and any specified molecules were involved in this process. Methods: Acquired resistant SK-BR-3 cells were established by chronic exposure to lapatinib or trastuzumab. Lapatinib or trastuzumab sensitivity were confirmed by MTT assay. Western blotting was used to determine signal transduction molecule changes. Wound healing assay and Boyden chamber assay were conducted for verifying invasive ability. Whole exome sequencing (WES) and siRNA knock-down system were used for further analysis. Results: Lapatinib resistant (LR) cell lines showed down-regulation of p-HER2, p-Akt, and p-Erk. The activity of Src family kinase was increased in LR cells. Vimentin, famous EMT marker, is also increased in LR cells. Migration and invasion were significantly increased in LR cells. Correlated with a missense mutation of RUNX3, which identified by WES, expression of RUNX3 was decreased in LR cells. Moreover, siRNA knock-down parental cells showed more resistance to lapatinib. Conclusion: The increase of Src activation, cell migration, and invasion was observed in LR cells. RUNX3, which identified by WES, affected to lapatinib sensitivity in SK-BR-3 cells. Therefore, RUNX3 might be a specified molecule, which partially contributes resistance to lapatinib. Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Dong Hyeon Ha, Hyemin Jang, Yu Jin Kim, Kyung-Hun Lee, Tae-Yong Kim, Seock-Ah Im. Acquired lapatinib resistant induces EMT-phenotype in breast cancer cells via Src and RUNX3 [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 4116. doi:10.1158/1538-7445.AM2017-4116