178P Targeting XPO1-dependent nuclear export of HMGB1 in non-small cell lung cancer

We looked at whether high-mobility group box 1 protein (HMGB1) is subject to exportin 1 (XPO1)-dependent nuclear export and whether HMGB1 mRNA levels predict response to immune checkpoint inhibitors (ICI) in NSCLC. RNA was isolated from NSCLC tumor patients. Gene expression analysis was conducted using NanoString Counter analysis system (PanCancer Immune Profiling Panel, capturing read counts of 784 genes). Western blotting analysis and cell viability assays in EGFR and KRAS-mutant cell lines were carried out. Evaluation of antitumoral effect of ICI in combination with selinexor and trametinib was determined in murine Lewis lung carcinoma model. High levels of HMGB1 mRNA in NSCLC patients receiving ICI were associated with progression-free survival (PFS) in exploratory (median PFS 9.0 versus 18.0 months, P = 0.008, hazard ratio = 0.30 in high versus low HMGB1) and validation (median PFS 18.1 versus 35.5 months, P = 0.029, hazard ratio = 0.39) cohorts. The combinations of erlotinib and osimertinib with selinexor in EGFR-mutant NSCLC cell lines (PC9 and H1975), and trametinib plus selinexor in KRAS-mutant NSCLC cell lines (A549, H460) were highly synergistic abolishing tumor cell proliferation. Consistent with this effect, the combination of trametinib with selinexor and/or PD-1 inhibitor highly inhibited tumor growth in the immune-resistant murine Lewis lung cancer model harbor KRAS G12C mutation. Our results suggest that the addition of selinexor as a blocker of HMGB1 nuclear export could overcome resistance to immunotherapy. The predictive value of HMGB1 mRNA was confirmed in metastatic NSCLC pretreatment samples treated with ICI. Overall, the pattern of reduced tumor growth induced by triple combination therapy (ICI, trametinib and/or selinexor) in the Lewis lung carcinoma model warrants further assessment in a clinical trial.