Abstract 3325: ERK inhibitor increases cancer stem cell population in NSCLC through Slug-Mediated epithelial-to-mesenchymal transition

Abstract

Abstract The aberrant activation of the Mitogen-activated protein kinase pathway (MAPK/ERK pathway) has been found to play an important role in many cancers including non-small-cell lung cancer (NSCLC). Multiple inhibitors targeting this pathway have been developed to treat cancer patients harboring the aberrant MAPK pathway genes. ERK inhibitors (ERKi) have been shown to be effective in a variety of solid-tumor malignancies, but like other MAPK inhibitors, they rarely confer complete and durable responses. Therefore, it is important to define the mechanism underlying potential tumor relapse following ERKi treatment. In this study, we found that ERKi treatment expanded the cancer stem cell (CSC) population in various NSCLC cell lines and a NSCLC patient-derived xenograft (PDX) harboring aberrant MAPK signaling. Such expansion of the CSC population is mainly caused by enhanced epithelial-to-mesenchymal transition (EMT)-mediated cancer cell dedifferentiation. Mechanistically, we revealed that ERK inhibition induces EMT via pSTAT3-mediated upregulation of EMT-transcription factor Slug. Specifically, we found that ERK inhibition increased phosphorylation of STAT3 at Y705, which further increased the expression of miR-204. Increased miR-204 then downregulated expression of SPDEF, a transcriptional repressor of Slug, thereby derepressing Slug expression. Moreover, we found that a low expression of Slug is necessary for maintaining stemness properties of CSCs. Thus, ERKi treatment-increased Slug must be downregulated to allow these cells to fully acquire stemness, and this process is mediated by a Slug-miR-200c negative feedback loop. Finally, we demonstrated that the JAK/STAT pathway inhibitor Ruxolitinib can block the ERK inhibitor-induced EMT and CSCs expansion, providing a feasible combination inhibitor approach for treating NSCLC patients. Overall, these studies provide a better understanding of the tumor relapse following ERKi treatment, and define the role of Slug in de novo production of CSCs and their maintenance. Citation Format: Shurui Cai, Na Li, Xuetao Bai, Ananya Banerjee, Lavudi Kousalya, Qi-en Wang. ERK inhibitor increases cancer stem cell population in NSCLC through Slug-Mediated epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3325.