Science translational medicine, 2018-06, Vol.10 (446)
2018
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- Autor(en) / Beteiligte
- Titel
- The ERBB network facilitates KRAS-driven lung tumorigenesis
- Ist Teil von
- Science translational medicine, 2018-06, Vol.10 (446)
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRAS -driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1946-6234eISSN: 1946-6242DOI: 10.1126/scitranslmed.aao2565Titel-ID: cdi_pubmed_primary_29925636
- Format
- –
- Schlagworte
- Adenocarcinoma of Lung - genetics, Adenocarcinoma of Lung - pathology, Animals, Apoptosis, Carcinogenesis - metabolism, Carcinogenesis - pathology, Cell Line, Tumor, Cell Proliferation, Disease Progression, ErbB Receptors - metabolism, Extracellular Signal-Regulated MAP Kinases - metabolism, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Humans, Lung Neoplasms - genetics, Lung Neoplasms - pathology, Mice, Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors, Mitogen-Activated Protein Kinase Kinases - metabolism, Mutation - genetics, Phosphorylation, Proto-Oncogene Proteins p21(ras) - metabolism, Signal Transduction, Survival Analysis