دورية أكاديمية
Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.
| العنوان: | Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors. |
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| المؤلفون: | Fernández-García F; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Fernández-Rodríguez A; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Fustero-Torre C; Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Piñeiro-Yáñez E; Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Wang H; School of Life Sciences and Technology, Tongji University, Shanghai 200092, China., Lechuga CG; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Callejas S; Genomic Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain., Álvarez R; Genomic Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain., López-García A; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Esteban-Burgos L; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Salmón M; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., San Román M; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Guerra C; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain.; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid 28029, Spain., Ambrogio C; Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy., Drosten M; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid 28029, Spain.; Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Salamanca 37007, Spain., Santamaría D; Molecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, Salamanca 37007, Spain., Al-Shahrour F; Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain., Dopazo A; Genomic Unit, Centro Nacional de Investigaciones Cardiovasculares, Madrid 28029, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid 28029, Spain., Barbacid M; Experimental Oncology Group, Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid 28029, Spain.; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid 28029, Spain., Musteanu M; Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Madrid 28029, Spain.; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid 28040, Spain.; Cancer and Obesity Group, Health Research Institute of San Carlos, Madrid 28040, Spain. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Sep 03; Vol. 121 (36), pp. e2402913121. Date of Electronic Publication: 2024 Aug 26. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Lung Neoplasms*/genetics , Lung Neoplasms*/immunology , Lung Neoplasms*/pathology , Proto-Oncogene Proteins p21(ras)*/genetics , Proto-Oncogene Proteins p21(ras)*/metabolism , Interferon Type I*/metabolism , Interferon Type I*/genetics , Signal Transduction* , Immune Checkpoint Inhibitors*/therapeutic use , Immune Checkpoint Inhibitors*/pharmacology , Mutation*, Animals ; Mice ; Humans ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; AMP-Activated Protein Kinase Kinases ; Cell Line, Tumor ; Tumor Microenvironment/immunology ; Tumor Microenvironment/genetics ; AMP-Activated Protein Kinases |
| مستخلص: | Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-β or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1. Competing Interests: Competing interests statement:The authors declare no competing interest. |
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| معلومات مُعتمدة: | RTI2018-094664-B-I00 Spanish Ministry of Science, Innovation and Universities; PID2021-122797OB-I00 Spanish Ministry of Science, Innovation and Universities |
| فهرسة مساهمة: | Keywords: KRAS; LKB1; interferon signaling pathway; lung cancer; p53 |
| المشرفين على المادة: | EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) 0 (Interferon Type I) 0 (Immune Checkpoint Inhibitors) 0 (KRAS protein, human) 0 (Tumor Suppressor Protein p53) EC 3.6.5.2 (Hras protein, mouse) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) EC 2.7.11.1 (STK11 protein, human) EC 2.7.11.1 (Stk11 protein, mouse) 0 (Trp53 protein, mouse) EC 2.7.11.31 (AMP-Activated Protein Kinases) |
| تواريخ الأحداث: | Date Created: 20240826 Date Completed: 20240826 Latest Revision: 20240914 |
| رمز التحديث: | 20240914 |
| مُعرف محوري في PubMed: | PMC11388366 |
| DOI: | 10.1073/pnas.2402913121 |
| PMID: | 39186651 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2402913121 |