The ERBB network facilitates KRAS-driven lung tumorigenesis
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Björn Kruspig Tiziana Monteverde Sarah Neidler Andreas Hock Emma Kerr Colin Nixon William Clark Ann Hedley Sarah Laing Seth B Coffelt John Le Quesne Craig Dick Karen Vousden Carla P Martins Daniel J MurphyAbstract
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.
Journal details
Journal Science Translational Medicine
Volume 10
Issue number 446
Pages eaao2565
Available online
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Publisher website (DOI) 10.1126/scitranslmed.aao2565
Europe PubMed Central 29925636
Pubmed 29925636
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