Inhibitor of Differentiation-1 Sustains Mutant -Driven Progression, Maintenance, and Metastasis of Lung Adenocarcinoma via Regulation of a FOSL1 Network.

Because of the refractory nature of mutant lung adenocarcinoma (LUAD) to current therapies, identification of new molecular targets is essential. Genes with a prognostic role in mutant 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 LUAD. Analysis of LUAD cohorts from TCGA and SPORE showed that high expression of was a marker of poor survival in patients harboring mutant, but not wild-type . Abrogation of Id1 induced G-M arrest and apoptosis in mutant LUAD cells. , loss of Id1 strongly impaired tumor growth and maintenance as well as liver metastasis, resulting in improved survival. Mechanistically, Id1 was regulated by the oncogene through JNK, and loss of Id1 resulted in downregulation of elements of the mitotic machinery via inhibition of the transcription factor FOSL1 and of several kinases within the signaling network. Our study provides clinical, functional, and mechanistic evidence underscoring as a critical gene in mutant 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 -mutant lung adenocarcinoma and provide mechanistic insight into how it controls tumor growth and metastasis.