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HMGB1 Expression Levels Correlate with Response to Immunotherapy in Non-Small Cell Lung Cancer
Maria González-Cao1, Xueting Cai2, Jilian Wilhelmina Paulina Bracht3
1Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Dexeus University Hospital, Barcelona, Spain.
Lung Cancer (Auckland, N.Z.)
|May 14, 2024
Summary
High HMGB1 mRNA expression in non-small cell lung cancer (NSCLC) patients predicts better response to immune checkpoint inhibitors (ICI). Targeting exportin 1 (XPO1) with selinexor enhances ICI efficacy in preclinical models.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- High-mobility group box 1 protein (HMGB1) is implicated in immunotherapy resistance.
- Exportin 1 (XPO1)-dependent nuclear export regulates HMGB1.
- Understanding HMGB1's role is crucial for improving NSCLC treatment.
Purpose of the Study:
- To investigate the association between HMGB1 mRNA expression and response to immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC).
Main Methods:
- RNA isolation from pretreatment NSCLC biopsies.
- Gene expression analysis of HMGB1 using NanoString.
- Western blotting, cell viability assays, and in vivo murine models.
Main Results:
- High HMGB1 mRNA levels correlated with significantly longer progression-free survival in NSCLC patients treated with ICI.
- Selinexor prevented HMGB1 nuclear export and, with targeted therapies, abolished tumor cell proliferation in EGFR/KRAS mutant cell lines.
- Combination therapy (selinexor, PD-1 inhibitor, trametinib) abrogated tumor growth in a murine Lewis lung cancer model.
Conclusions:
- HMGB1 mRNA expression is a predictive biomarker for ICI response in NSCLC.
- Targeting XPO1 with selinexor represents a promising strategy to overcome immunotherapy resistance.
- Further research into HMGB1 functions may reveal novel therapeutic targets for metastatic NSCLC.
