Oncogenic Kras Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17
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Abstract
Oncogenic mutations in Kras occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-α and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-α shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity. Cancer Res; 71(3); 1071–80. ©2010 AACR.
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“Acquired AZ’1569-R clones overproduce a wide array of proinflammatory factors We have previously shown that oncogenic KRAS regulates growth factor and/or cytokine shedding andADAM17 activity (30), a protease involved in acute resistance to chemotherapy and targeted therapies (31).”
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- Authors
- Van Schaeybroeck, S., Kyula, J. N., Fenton, A., Fenning, C. S., Sasazuki, T., Shirasawa, S., Longley, D. B., & Johnston, P. G.
- Affiliations
- Authors' Affiliations: 1Drug Resistance Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland; and 2Institute for Advanced Study, Kyushu University, Higashi-ku, and 3Department of Cell Biology, Faculty of Medicine, Fukuoka University, Jonan-Ku, Fukuoka, Japan
- Queen's University Belfast (GB)
- Corresponding author
- Johnston, Patrick G.
- Venue
- Cancer Research
- Published
- 2011-02-01
- Volume
- 71
- Issue
- 3
- Pages
- 1071-1080
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3073126
- OpenAlex
- W2057940570
- Cited by
- 51
- References
- 29
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2022: 2 · 2021: 6 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 5 · 2012: 3
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- AstraZeneca
- Cancer Research UK (A7261, A5862)
- Public Health Agency (RRG/3261/05)
- Japan Society for the Promotion of Science (21390102, 22133009)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- oncogenic KRAS, ADAM17, colorectal cancer, chemoresistance, MEK1/2 inhibition, ERK signaling, transforming growth factor-alpha, vascular endothelial growth factor, HCT116 cells, apoptosis, xenograft tumor growth
- MeSH terms
- Cetuximab, ADAM17 Protein, Gefitinib, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Humans, Mice, Inbred BALB C, Proto-Oncogene Proteins, Quinazolines, Genes, ras, Colorectal Neoplasms, Transforming Growth Factor alpha, Proto-Oncogene Proteins p21(ras), Mice, SCID, Point Mutation, ras Proteins, HT29 Cells, HCT116 Cells, Cell Line, Tumor, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mice, ADAM Proteins, Antibodies, Monoclonal, Humanized
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