Abstract 3104: EMT and CSC Enrichment Induced by ERK Inhibition in NSCLC

Abstract

Abstract The activation of Mitogen-activated protein kinase pathway (MAPK/ERK pathway) has been found to play an important role in many cancers including lung cancer, and multiple inhibitors targeting this pathway have been developed. Several ERK inhibitors (ERKi, e.g., Ulixertinib, SCH772984) have been shown to be active against different cancers harboring RAS, BRAF, or MEK mutations, as well as cancers with developed BRAF/MEK inhibitor resistance. Nevertheless, sustained inhibition of ERK can lead to resistance and is likely to cause tumor relapse as well. Studies over the years have shown that a small portion of cells within tumors, which can reproduce themselves and sustain cancer, being called “cancer stem cells (CSCs)”, is the cause of tumor initiation and progression. Many reports have implicated the association of Epithelial-to-Mesenchymal Transition (EMT) program with CSCs and identified EMT-transcription factors (TFs) as CSC regulators. Here, we demonstrated that ERKi treatment induces EMT in non-small cell lung cancer cells (NSCLC), probably by inducing Slug expression. We also found that ERKi treatment can enrich the cancer stem cell (CSC) like population in NSCLC cells, evidenced by increased ALDH+ cells, enhanced in vitro sphere formation capability, and enhanced tumorigenicity in immunodeficient mice. Moreover, in NSCLC cells, we proved ERK knockdown or ERKi treatment can reduce C/EBPα expression, which is believed to be a master epithelial “gatekeeper” whose expression is required to prevent unwarranted mesenchymal transition. Our findings reveal a novel mechanism underlying the tumor relapse after ERKi treatment in NSCLC, and ultimately will help us improve current NSCLC therapeutic methods. Citation Format: Shurui Cai, Xuetao Bai, Na Li, Ananya Banerjee, Kousalya Lavudi, Tejinder Pal. EMT and CSC Enrichment Induced by ERK Inhibition in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3104.