TY - JOUR
T1 - HMGB1 Expression Levels Correlate with Response to Immunotherapy in Non-Small Cell Lung Cancer
AU - González-Cao, Maria
AU - Cai, Xueting
AU - Bracht, Jilian Wilhelmina Paulina
AU - Han, Xuan
AU - Yang, Yang
AU - Pedraz-Valdunciel, Carlos
AU - Morán, Teresa
AU - García-Corbacho, Javier
AU - Aguilar, Andrés
AU - Bernabé, Reyes
AU - De Marchi, Pedro
AU - da Silva, Luciane Sussuchi
AU - Leal, Leticia Ferro
AU - Reis, Rui Manuel
AU - Codony-Servat, Jordi
AU - Jantus-Lewintre, Eloisa
AU - Molina-Vila, Miguel Angel
AU - Cao, Peng
AU - Rosell, Rafael
N1 - Publisher Copyright:
© 2024 González-Cao et al.
PY - 2024/5/1
Y1 - 2024/5/1
N2 - Purpose: 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). Patients and Methods: 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. Results: 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. Conclusion: 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.
AB - Purpose: 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). Patients and Methods: 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. Results: 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. Conclusion: 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.
KW - HMGB1
KW - immunotherapy
KW - K-Ras mutations
KW - Lewis lung cancer murine model
KW - non-small cell lung cancer
UR - http://www.scopus.com/inward/record.url?scp=85193700937&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/0302ac0b-06c5-3bfc-9006-caed2de6cecf/
UR - https://portalrecerca.uab.cat/en/publications/db344bf4-8c09-474d-a34b-a6f41bec82d5
U2 - 10.2147/LCTT.S455034
DO - 10.2147/LCTT.S455034
M3 - Article
C2 - 38741920
AN - SCOPUS:85193700937
SN - 1179-2728
VL - 15
SP - 55
EP - 67
JO - Lung Cancer: Targets and Therapy
JF - Lung Cancer: Targets and Therapy
ER -
