The ERBB network facilitates KRAS-driven lung tumorigenesis

Kruspig, B. et al. (2018) The ERBB network facilitates KRAS-driven lung tumorigenesis. Science Translational Medicine, 10(446), eaao2565. (doi: 10.1126/scitranslmed.aao2565) (PMID:29925636)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vousden, Karen and Nixon, Mr Colin and Coffelt, Dr Seth and Clark, Mr William and Le Quesne, Professor John and Monteverde, Tiziana and Murphy, Dr Daniel and Neidler, Ms Sarah and Kruspig, Dr Bjorn and Hock, Dr Andreas
Authors: 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., and Murphy, D. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Science Translational Medicine
Publisher:American Association for the Advancement of Science
ISSN:1946-6234
ISSN (Online):1946-6242
Copyright Holders:Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
First Published:First published in Science Translational Medicine 10(446):eaao2565
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
632881SERPLUC: Suppression of Enzymes Required for Progression of Lung CancerDaniel MurphyEuropean Commission (EC)618448RI CANCER SCIENCES
631971A versatile spatio-temporally inducible genetically engineered mouse model of mesotheliomaDaniel MurphyBritish Lung Foundation (BLF)APHD13-5RI CANCER SCIENCES
717931NuSiCCDaniel MurphyEuropean Commission (EC)705190RI CANCER SCIENCES