Abstract 4761: BCL2 induced by LAMTOR3-MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer

Abstract

Abstract Metastasis and chemoresistance, which are main causes of lung cancer related death, have been major interest in cancer research. Recently, Epithelial-Mesenchymal Transition (EMT) a foremost process for acquiring metastatic properties has been demonstrated to be strongly link to chemoresistance. Due to limited understanding of mechanism for EMT mediated chemoresistance, druggable targets for chemoresistance remained unidentified yet. In this study, we established the mesenchymal like cancer cells (MLCCs) from A549 lung cancer cells with chronic exposure of TGFβ. With clinicogenomics database analysis and following validation with MLCC model, we determined that BCL2, of which expression was clearly induced and indicated a poor prognosis in the mesenchymal cancer patients, was responsible for high chemoresistance in MLCCs. Therefore combined treatment of chemotherapeutic drug and BH3 mimetic such as ABT-263 or ABT-737, remarkably sensitized MLCCs to chemo and radio therapy. Furthermore, BCL2 expression was governed by sustained ERK1 activity in MLCCs, which resulted from high level of MEK partner-1 (MP1) protein expression. Therefore, combined chemotherapy with small molecules (approved by FDA or clinically tested) targeting for MEK1 or BCL2 would be a clinically feasible approach to overcome EMT related chemoresistance. Citation Format: Ok-Seon Kwon, Soon-Ki Hong, Hyuk-Jin Cha. BCL2 induced by LAMTOR3-MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer [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 4761. doi:10.1158/1538-7445.AM2017-4761