HMGB1 Expression Levels Correlate with Response to Immunotherapy in Non-Small Cell Lung Cancer
González-Cao, Maria (Hospital Universitari Dexeus (Barcelona, Catalunya))
Cai, Xueting (Nanjing University of Chinese Medicine)
Paulina Bracht, Jilian Wilhelmina (Amsterdam University Medical Center (UMC))
Han, Xuan (Nanjing University of Chinese Medicine)
Yang, Yang (Nanjing University of Chinese Medicine)
Pedraz-Valdunciel, Carlos (Hospital Universitari Dexeus (Barcelona, Catalunya))
Morán, Teresa (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
García-Corbacho, Javier (Hospital Clínic i Provincial de Barcelona)
Aguilar, Andrés (Hospital Universitari Dexeus (Barcelona, Catalunya))
Bernabé, Reyes (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
De Marchi, Pedro (Barretos Cancer Hospital)
da Silva, L.S. (Barretos Cancer Hospital)
Leal, L.F. (Barretos Cancer Hospital)
Reis, R.M. (ICVS/3b's - PT Government Associate Laboratory)
Codony-Servat, Jordi (Hospital Universitari Dexeus (Barcelona, Catalunya))
Jantus-Lewintre, E. (Universitat Politècnica de València)
Molina-Vila, M.A. (Hospital Universitari Dexeus (Barcelona, Catalunya))
Cao, P. (Nanjing University of Chinese Medicine)
Rosell, Rafael (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Universitat Autònoma de Barcelona

Fecha:	2024
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	HMGB1 ; K-Ras mutations ; Lewis lung cancer murine model ; Immunotherapy ; Non-small cell lung cancer
Publicado en:	Lung Cancer: Targets and Therapy, Vol. 15 (2024) , p. 55-67, ISSN 1179-2728

DOI: 10.2147/LCTT.S455034
PMID: 38741920

13 p, 5.2 MB

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Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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