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The ERBB network facilitates KRAS-driven lung tumorigenesis
Open accessPublished version of a preprint
Abstract
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. Here we show that initiation and progression of KRAS-driven lung tumors requires input from ERBB family 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 G12D -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 . Importantly, brief pharmacological inhibition of the ERBB network significantly enhances the therapeutic benefit of MEK 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. One Sentence Summary G12 Mutant KRAS requires tonic ERBB network activity for initiation and maintenance of lung cancer
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“Indeed, pan-ERBB inhibition enhanced the potency of MEK inhibition in vitro and in vivo.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [61]
In the citing paper
“ERBB activity establishes a feed-forward loop to amplify signaling through the core RAS-ERK cascade to sustain survival and proliferation in KRAS-mutant NSCLC.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [61]
In the citing paper
“multiple ERBB ligands (e.g., Areg, Ereg, Nrg3, Nrg4, and Hbegf) and receptors (for example, Erbb2 and Erbb3) were highly expressed in a KRASG12D mouse model.”
From New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness (2019) · cites this paper as [61]
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Metadata
- 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. H., Martins, C. P., & Murphy, D. J.
- Affiliations
- University of Glasgow (GB)
- Cancer Research UK Scotland Institute (GB)
- MRC Cancer Unit (GB)
- MRC Toxicology Unit, Leicester LE1 7HB, UK.
- National Health Service (GB)
- Corresponding author
- Kruspig, Björn
- Monteverde, Tiziana
- Murphy, Daniel J.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2018-06-20
- Volume
- 10
- Issue
- 446
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC6881183
- OpenAlex
- W2809593667
- Cited by
- 111
- References
- 47
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 8 · 2023: 12 · 2022: 14 · 2021: 19 · 2020: 16 · 2019: 15 · 2018: 6
- FWCI
- 10.54
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science Translational Medicine (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- Funders
- Medical Research Council (5TS30)
- British Lung Foundation (APHD13-5, CSOBLF RG16-2)
- European Commission (CIG 618448, 705190 “NuSiCC”)
- Deutsche Krebshilfe (109220)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS mutation, lung cancer, lung carcinogenesis, Ras signaling, MEK inhibition, combination therapy, tumor progression, cell proliferation
- MeSH terms
- Adenocarcinoma of Lung, Animals, Humans, Lung Neoplasms, Mutation, Phosphorylation, Signal Transduction, Gene Expression Regulation, Neoplastic, Survival Analysis, Proto-Oncogene Proteins p21(ras), Apoptosis, Disease Progression, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Mice, Gene Regulatory Networks, Carcinogenesis, ErbB Receptors
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