The ERBB network facilitates KRAS-driven lung tumorigenesis

    Research output: Contribution to journalArticle

    • 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
    Journal publication date20 Jun 2018
    Issue number446
    Publication statusPublished - 20 Jun 2018
    Externally publishedYes

    ID: 154792878