Inhibitor of differentiation-1 (Id1) sustains mutant KRAS-driven progression, maintenance, and metastasis of lung adenocarcinoma via regulation of a FOSL1 network
Román M (1), López I (1), Guruceaga E (2), Baraibar I (3), Ecay M (4), Collantes M (4), Nadal E (5), Vallejo A (1), Cadenas S (6), Echávarri-de Miguel M (6), Jang JH (7), San Martín-Uriz P (8), Castro-Labrador L (9), Vilas-Zornoza A (10), Lara-Astiaso D (11), Ponz-Sarvise M (12), Rolfo C (13), Santos ES (14), Raez LE (15), Taverna S (16), Behrens C (17), Weder W (18), Wistuba II (19), Vicent S (20), Gil-Bazo I (21).
(1) Program of Solid Tumors and Biomarkers, Center for Applied Medical Research.
(2) Bioinformatics Platform, CIMA, University of Navarra.
(3) Department of Oncology, Clínica Universidad de Navarra.
(4) Nuclear Medicine, Clínica Universidad de Navarra.
(5) Medical Oncology, Catalan Institute of Oncology.
(6) Program of Solid Tumors, Center for Applied Medical Research.
(7) Department of Thoracic Surgery, University Hospital of Zurich.
(8) Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA).
(9) Oncohematology, Center for Applied Medical Research (CIMA).
(10) Advanced Genomics, Center for Applied Medical Research (CIMA).
(11) Center for Applied Medical Research, Advanced Genomics Laboratory, University of Navarra.
(12) Medical Oncology, Clinica Universidad de Navarra/Center for Applied Medical Research (CIMA), University of Navarra.
(13) Thoracic Medical Oncology and Early Clinical Trials, Marlene and Stweart Greenebaum Comprehensive Cancer Center.
(14) Lynn Cancer Institute.
(15) Medical Director, Memorial Cancer Institute, Memorial Health Care System.
(16) Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council.
(17) Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center.
(18) Division of Thoracic Surgery, University Hospital Zürich.
(19) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center.
(20) Program of Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra.
(21) Department of Oncology, Clínica Universidad de Navarra
Due to 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 LUAD patients.
CITATION Cancer Res. 2018 Dec 18. pii: canres.1479.2018. doi: 10.1158/0008-5472.CAN-18-1479