PDF(Pubmed)
Abstract：
UNASSIGNED: High-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export, and it is involved in functions implicated in resistance to immunotherapy. We investigated whether HMGB1 mRNA expression was associated with response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC).
UNASSIGNED: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model.
UNASSIGNED: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model.
UNASSIGNED: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.
UNASSIGNED: RNA was isolated from pretreatment biopsies of patients with advanced NSCLC treated with ICI. Gene expression analysis of several genes, including HMGB1, was conducted using the NanoString Counter analysis system (PanCancer Immune Profiling Panel). Western blotting analysis and cell viability assays in EGFR and KRAS mutant cell lines were carried out. Evaluation of the antitumoral effect of ICI in combination with XPO1 blocker (selinexor) and trametinib was determined in a murine Lewis lung carcinoma model.
UNASSIGNED: HMGB1 mRNA levels in NSCLC patients treated with ICI correlated with progression-free survival (PFS) (median PFS 9.0 versus 18.0 months, P=0.008, hazard ratio=0.30 in high versus low HMGB1). After TNF-α stimulation, HMGB1 accumulates in the cytoplasm of PC9 cells, but this accumulation can be prevented by using selinexor or antiretroviral drugs. Erlotinib or osimertinib with selinexor in EGFR-mutant cells and trametinib plus selinexor in KRAS mutant abolish tumor cell proliferation. Selinexor with a PD-1 inhibitor with or without trametinib abrogates the tumor growth in the murine Lewis lung cancer model.
UNASSIGNED: An in-depth exploration of the functions of HMGB1 mRNA and protein is expected to uncover new potential targets and provide a basis for treating metastatic NSCLC in combination with ICI.
摘要：
■高迁移率族蛋白1（HMGB1）受输出蛋白1（XPO1）依赖的核输出，它参与了与免疫疗法抗性有关的功能。我们研究了HMGB1mRNA表达是否与非小细胞肺癌（NSCLC）对免疫检查点抑制剂（ICI）的反应相关。
■从用ICI治疗的晚期NSCLC患者的预处理活检中分离RNA。几个基因的基因表达分析，包括HMGB1,使用NanoString计数器分析系统(PanCancer免疫分析小组)进行。在EGFR和KRAS突变细胞系中进行蛋白质印迹分析和细胞活力测定。在鼠Lewis肺癌模型中确定ICI与XPO1阻断剂(selinexor)和曲美替尼组合的抗肿瘤作用的评估。
■接受ICI治疗的非小细胞肺癌患者的HMGB1mRNA水平与无进展生存期（PFS）相关（中位PFS9.0与18.0个月，P=0.008，高与低HMGB1的风险比=0.30）。TNF-α刺激后，HMGB1在PC9细胞的细胞质中积累，但是这种积累可以通过使用selinexor或抗逆转录病毒药物来预防。EGFR突变细胞中的厄洛替尼或奥希替尼联合selinexor和KRAS突变细胞中的曲美替尼联合selinexor消除肿瘤细胞增殖。Selinexor与PD-1抑制剂一起使用或不使用曲美替尼可以消除小鼠Lewis肺癌模型中的肿瘤生长。
■对HMGB1mRNA和蛋白功能的深入探索有望发现新的潜在靶点，为联合ICI治疗转移性NSCLC提供依据。
■从用ICI治疗的晚期NSCLC患者的预处理活检中分离RNA。几个基因的基因表达分析，包括HMGB1,使用NanoString计数器分析系统(PanCancer免疫分析小组)进行。在EGFR和KRAS突变细胞系中进行蛋白质印迹分析和细胞活力测定。在鼠Lewis肺癌模型中确定ICI与XPO1阻断剂(selinexor)和曲美替尼组合的抗肿瘤作用的评估。
■接受ICI治疗的非小细胞肺癌患者的HMGB1mRNA水平与无进展生存期（PFS）相关（中位PFS9.0与18.0个月，P=0.008，高与低HMGB1的风险比=0.30）。TNF-α刺激后，HMGB1在PC9细胞的细胞质中积累，但是这种积累可以通过使用selinexor或抗逆转录病毒药物来预防。EGFR突变细胞中的厄洛替尼或奥希替尼联合selinexor和KRAS突变细胞中的曲美替尼联合selinexor消除肿瘤细胞增殖。Selinexor与PD-1抑制剂一起使用或不使用曲美替尼可以消除小鼠Lewis肺癌模型中的肿瘤生长。
■对HMGB1mRNA和蛋白功能的深入探索有望发现新的潜在靶点，为联合ICI治疗转移性NSCLC提供依据。
