EOAI3402143 inhibits lung adenocarcinoma progression through the NF-κB/NR4A1 pathway

Abstract

Lung adenocarcinoma (LUAD) is currently the cancer with the highest morbidity and mortality rates in the world, and its targeted therapy, although effective, is limited in the types of targeted drugs and prone to drug resistance in treated patients. Therefore, the continuous discovery of new targeted therapeutic agents is particularly crucial for the treatment of LUAD. Here, we aim to investigate the antitumor effect of EOAI3402143 on LUAD and the potential mechanism of its action. We use flow cytometry to analyze apoptosis, transwell and colony formation assays to detect cell migration, invasion and proliferation ability; western blot, RT-qPCR and RNA-seq to analyze the signaling pathways involved in EOAI3402143; and in vivo experiments to test the therapeutic effect of EOAI3402143 on LUAD. Our results show that EOAI3402143 promotes apoptosis and inhibits the migration, invasion and proliferation of LUAD cells. Mechanistic studies reveal that EOAI3402143 inhibits the activation of the NF-κB pathway and suppresses the expression of NR4A1, which in turn inhibits the progression of LUAD. In vivo experiments reveal that EOAI3402143 has a better therapeutic effect on LUAD. These findings indicate that EOAI3402143 has significant antitumor efficacy against LUAD and is promising as a new therapeutic agent for LUAD.

1. Introduction

Lung cancer is one of the common malignant tumors that threatens human life and health, with high morbidity and mortality. Lung cancer is mainly divided into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), of which NSCLC accounts for approximately 80%–85% of cases [1–3]. NSCLC includes lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), and large cell carcinoma (LCC), of which lung adenocarcinoma is the cancer with the highest mortality rate among lung cancers [4]. Despite great advances in the diagnostic methods and treatment of LUAD in recent years, most patients experience local spread and distant metastases, and the prognosis remains poor, with a five-year survival rate of only approximately 15% [5]. This grim prognosis is due to advanced disease manifestations, heterogeneous tumor characteristics with multiple histological subtypes and our poor understanding of tumor biology [6]. A molecular classification of lung adenocarcinoma subgroups has been established, the most common of which are KRAS mutations and EGFR mutations [7]. Lung adenocarcinomas with different mutation types have different sensitivities to drugs; therefore, personalized therapeutic agents are needed for the treatment of lung adenocarcinomas.

Although great progress has been made in targeted therapy for LUAD in recent years, some types of mutated lung adenocarcinomas for which there are no suitable targeted drugs exist, and even if there are, it is extremely common for patients to develop resistance to targeted drugs, and their five-year survival rate is still low [8]. After exhausting the available targeted agents, patients are usually treated with nontargeted, systemic cytotoxic regimens with unsatisfactory results [9]. Therefore, finding new potential therapeutic agents with antitumor efficacy and low toxicity for LUAD patients is particularly important to address this dilemma. EOAI3402143 is a novel small-molecule compound that we identified through screening a 600-compound small-molecule library. As a typical small-molecule agent, EOAI3402143 can penetrate cell membranes and interact with specific intracellular targets. Small-molecule targeted drugs offer precise action against diseased cells while minimizing damage to normal cells, featuring high efficacy, low toxicity, and convenient administration, making them an important approach for personalized LUAD treatment. Current research on EOAI3402143 remains limited. Although existing studies have demonstrated its tumor-suppressive activity in NSCLC, the precise molecular mechanisms remain unclear. Our study aimed to elucidate these underlying mechanisms [10–12].