The ERBB network facilitates KRAS-driven lung tumorigenesis

• Published in: Science translational medicine Vol. 10; no. 446
• Main Authors: Kruspig, Björn, Monteverde, Tiziana, Neidler, Sarah, Hock, Andreas, Kerr, Emma, Nixon, Colin, Clark, William, Hedley, Ann, Laing, Sarah, Coffelt, Seth B, Le Quesne, John, Dick, Craig, Vousden, Karen H, Martins, Carla P, Murphy, Daniel J
• Format: Journal Article
• Language: English
• Published: United States 20.06.2018
• Subjects: 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
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aao2565

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.