The ERBB network facilitates KRAS-driven lung tumorigenesis

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 Murphy

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Abstract

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 KRASG12D-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.

Original languageEnglish
JournalScience Translational Medicine
Volume10
Issue number446
DOIs
Publication statusPublished - 20 Jun 2018
Externally publishedYes

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Kruspig, B., Monteverde, T., Neidler, S., Hock, A., Kerr, E., Nixon, C., ... Murphy, D. J. (2018). The ERBB network facilitates KRAS-driven lung tumorigenesis. Science Translational Medicine, 10(446). https://doi.org/10.1126/scitranslmed.aao2565