Osimertinib resistance-based immune prognostic related gene signature in EGFR mutant lung adenocarcinoma, in which PSMD11 promotes tumor progression

Abstract

Background At present, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment, as the first-line treatment of lung adenocarcinoma (LUAD) with EGFR mutation, has achieved good clinical efficacy, but most patients will eventually develop acquired resistance. Therefore, there is an urgent need to develop a strong standard to identify drug-resistant patients with EGFR mutation who can benefit from other treatments. Methods Based on the differentially expressed genes between osimertinib (OSI)-resistant cells (PC9OR, H1975OR) and non OSI-resistant LUAD cells (PC9, H1975), the EGFR mutant LUAD prognosis related genes from TCGA database, and the immune genes from ImmPort and InnateDB websites, we constructed an immune prognosis model of OSI resistance to predict the outcome of EGFR mutant LUAD patients. Then, according to the risk score, EGFR mutant LUAD patients were divided into high- and low-risk groups, and the molecular, immune characteristics and responsiveness to chemotherapy and targeted drugs were analyzed. Next, PSMD11 was knocked down using siRNA to evaluate the effects of PSMD11 on PC9OR and H1975OR cells. Finally, the correlation between PSMD11 and OSI resistance was determined in vitro via CCK-8, colony formation assays and flow cytometry, and in vivo via western blot and immunohistochemistry. Results We constructed an immune prognostic prediction model consisting of four OSI-resistant genes (C3, PSMD11, G3BP1, TRIB2), and clarified its accuracy in predicting the prognosis of EGFR mutant LUAD patients. According to the risk score classification, high-risk EGFR mutant patients were more sensitive to traditional chemotherapy and targeted drugs, with higher expression of immune checkpoints PD-1, LAG3, IDO1, and more infiltration of CD8 + T cells, M0/M1 macrophages and NK cells. In addition, knockdown of PSMD11 could inhibit cell proliferation, promote cell apoptosis, and increase the sensitivity of drug-resistant cells to OSI. And compared with individual treatment, the combination treatment of PSMD11-siRNA and OSI in PC9OR and H1975OR cells could significantly inhibit cell proliferation and promote tumor growth. In addition, PSMD11 could promote the progression of OSI-resistant LUAD by activating the NF-κB/IL-6/STAT3 signaling pathway. Conclusions our work provide a powerful prediction tool for further screening OSI-resistant LUAD patients suitable for chemotherapy, targeted therapy and immunotherapy.