Detalle Publicación

Inhibitor of differentiation-1 sustains mutant KRAS-driven progression, maintenance, and metastasis of lung adenocarcinoma via regulation of a FOSL1 network

Autores: Roman, M.; López Erdozain, María Inés; Guruceaga Martínez, Elisabet; Baraibar Argota, Iosune; Ecay Ilzarbe, Marga; Collantes Martínez, María; Nadal, E.; Vallejo Blanco, Adrián; Cadenas, S.; Echavarri, M.; Jang, J. H.; San Martín Úriz, Patxi; Castro-Labrador, L.; Vilas Zornoza, Amaia; Lara-Astiaso, D.; Ponz Sarvisé, Mariano; Rolfo, C.; Santos, E. S.; Raez, L. E.; Taverna, S.; Behrens, C.; Weder, W.; Wistuba, I. I.; Vicent Cambra, Silvestre; Gil Bazo, Ignacio
Título de la revista: CANCER RESEARCH
ISSN: 0008-5472
Volumen: 79
Número: 3
Páginas: 625 - 638
Fecha de publicación: 2019
Because of the refractory nature of mutant KRAS lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant KRAS LUAD have proven to be potential molecular targets for therapeutic development. Here we determine the clinical, functional, and mechanistic role of inhibitor of differentiation-1 (Id1) in mutant KRAS LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of Id1 was a marker of poor survival in patients harboring mutant, but not wild-type KRAS. Abrogation of Id1 induced G(2)-M arrest and apoptosis in mutant KRAS LUAD cells. In vivo, loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the KRAS oncogene through JNK, and loss of Id1 resulted in down-regulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the KRAS signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring Id1 as a critical gene in mutant KRAS LUAD and warrants further studies of Id1 as a therapeutic target in patients with LUAD. Significance: These findings highlight the prognostic significance of the transcriptional regulator Id1 in KRAS-mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.