González-Cao Maria, Cai Xueting, Bracht Jilian Wilhelmina Paulina, Han Xuan, Yang Yang, Pedraz-Valdunciel Carlos, Morán Teresa, García-Corbacho Javier, Aguilar Andrés, Bernabé Reyes, De Marchi Pedro, Sussuchi da Silva Luciane, Leal Leticia Ferro, Reis Rui Manuel, Codony-Servat Jordi, Jantus-Lewintre Eloisa, Molina-Vila Miguel Angel, Cao Peng, Rosell Rafael
Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain.
Integrated Traditional Chinese and Western Medicine Department of Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People's Republic of China.
Lung Cancer (Auckl). 2024 May 9;15:55-67. doi: 10.2147/LCTT.S455034. eCollection 2024.
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).
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.
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.
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.
高迁移率族蛋白B1（HMGB1）可通过核输出蛋白1（XPO1）依赖的方式进行核输出，且参与免疫治疗耐药相关的功能。我们研究了HMGB1 mRNA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。
从接受ICI治疗的晚期NSCLC患者的治疗前活检组织中分离RNA。使用NanoString计数分析系统（泛癌免疫分析面板）对包括HMGB1在内的多个基因进行基因表达分析。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。在小鼠Lewis肺癌模型中确定ICI联合XPO1阻断剂（塞利尼索）和曲美替尼的抗肿瘤效果。
接受ICI治疗的NSCLC患者中，HMGB1 mRNA水平与无进展生存期（PFS）相关（高HMGB1组与低HMGB1组的中位PFS分别为9.0个月和18.0个月，P = 0.008，风险比 = 0.30）。TNF-α刺激后，HMGB1在PC9细胞的细胞质中积累，但使用塞利尼索或抗逆转录病毒药物可阻止这种积累。EGFR突变细胞中，厄洛替尼或奥希替尼与塞利尼索联合，以及KRAS突变细胞中曲美替尼加塞利尼索可抑制肿瘤细胞增殖。塞利尼索与PD-1抑制剂联合使用（无论是否添加曲美替尼）可抑制小鼠Lewis肺癌模型中的肿瘤生长。
深入探索HMGB1 mRNA和蛋白质的功能有望发现新的潜在靶点，并为联合ICI治疗转移性NSCLC提供依据。
