2026-08-05T15:04:38Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/267862025-12-18T12:57:24Zcom_20.500.12105_2327com_20.500.12105_2290col_20.500.12105_16991

00925njm 22002777a 4500 dc Fernández-García, Fernando author Fernández-Rodríguez, Ana author Fustero-Torre, Coral author Piñeiro-Yáñez, Elena author Wang, Haiyun author Lechuga, Carmen G author Callejas, Sergio author Álvarez, Rebeca author López-García, Alejandra author Esteban-Burgos, Laura author Salmón, Marina author San Román, Marta author Guerra, Carmen author Ambrogio, Chiara author Drosten, Matthias author Santamaría, David author Al-Shahrour, Fatima author Dopazo, Ana author Barbacid, Mariano author Musteanu, Mónica author 2024-09-03 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 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. Proc Natl Acad Sci U S A . 2024 Sep 3;121(36):e2402913121. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 39186651 https://hdl.handle.net/20.500.12105/26786 KRAS LKB1 interferon signaling pathway lung cancer p53 Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.