RT Journal Article
SR Electronic
T1 Inhibitor of Differentiation-1 Sustains Mutant <em>KRAS</em>-Driven Progression, Maintenance, and Metastasis of Lung Adenocarcinoma via Regulation of a FOSL1 Network
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 625
OP 638
DO 10.1158/0008-5472.CAN-18-1479
VO 79
IS 3
A1 Román, Marta
A1 López, Inés
A1 Guruceaga, Elisabeth
A1 Baraibar, Iosune
A1 Ecay, Margarita
A1 Collantes, María
A1 Nadal, Ernest
A1 Vallejo, Adrián
A1 Cadenas, Silvia
A1 Miguel, Marta Echavarri-de
A1 Jang, Jae Hwi
A1 Martin-Uriz, Patxi San
A1 Castro-Labrador, Laura
A1 Vilas-Zornoza, Amaia
A1 Lara-Astiaso, David
A1 Ponz-Sarvise, Mariano
A1 Rolfo, Christian
A1 Santos, Edgardo S.
A1 Raez, Luis E.
A1 Taverna, Simona
A1 Behrens, Carmen
A1 Weder, Walter
A1 Wistuba, Ignacio I.
A1 Vicent, Silvestre
A1 Gil-Bazo, Ignacio
YR 2019
UL http://cancerres.aacrjournals.org/content/79/3/625.abstract
AB 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 G2–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 downregulation 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.