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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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
Issue number446
Publication statusPublished - 20 Jun 2018
Externally publishedYes


Cite this

Kruspig, B., Monteverde, T., Neidler, S., Hock, A., Kerr, E., Nixon, C., Clark, W., Hedley, A., Laing, S., Coffelt, S. B., Le Quesne, J., Dick, C., Vousden, K., Martins, C. P., & Murphy, D. J. (2018). The ERBB network facilitates KRAS-driven lung tumorigenesis. Science Translational Medicine, 10(446).