Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17

Sandra Van Schaeybroeck, Joan N. Kyula, Audrey Fenton, Catherine S. Fenning, Takehiko Sasazuki, Senji Shirasawa, Daniel B. Longley, Patrick G. Johnston

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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.

Original languageEnglish
Pages (from-to)1071-1080
Number of pages10
JournalCancer Research
Volume71
Issue number3
DOIs
Publication statusPublished - Feb 1 2011

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Intercellular Signaling Peptides and Proteins
Drug Therapy
Colorectal Neoplasms
HCT116 Cells
Mitogen-Activated Protein Kinase 3
Growth Factor Receptors
ADAM17 Protein
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase Kinases
Drug Resistance
Heterografts
Vascular Endothelial Growth Factor A
Apoptosis
Ligands
Cell Line
Mutation
Growth
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Van Schaeybroeck, S., Kyula, J. N., Fenton, A., Fenning, C. S., Sasazuki, T., Shirasawa, S., ... Johnston, P. G. (2011). Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17. Cancer Research, 71(3), 1071-1080. https://doi.org/10.1158/0008-5472.CAN-10-0714

Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17. / Van Schaeybroeck, Sandra; Kyula, Joan N.; Fenton, Audrey; Fenning, Catherine S.; Sasazuki, Takehiko; Shirasawa, Senji; Longley, Daniel B.; Johnston, Patrick G.

In: Cancer Research, Vol. 71, No. 3, 01.02.2011, p. 1071-1080.

Research output: Contribution to journalArticle

Van Schaeybroeck, S, Kyula, JN, Fenton, A, Fenning, CS, Sasazuki, T, Shirasawa, S, Longley, DB & Johnston, PG 2011, 'Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17', Cancer Research, vol. 71, no. 3, pp. 1071-1080. https://doi.org/10.1158/0008-5472.CAN-10-0714
Van Schaeybroeck S, Kyula JN, Fenton A, Fenning CS, Sasazuki T, Shirasawa S et al. Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17. Cancer Research. 2011 Feb 1;71(3):1071-1080. https://doi.org/10.1158/0008-5472.CAN-10-0714
Van Schaeybroeck, Sandra ; Kyula, Joan N. ; Fenton, Audrey ; Fenning, Catherine S. ; Sasazuki, Takehiko ; Shirasawa, Senji ; Longley, Daniel B. ; Johnston, Patrick G. / Oncogenic Kras promotes chemotherapy-induced growth factor shedding via ADAM17. In: Cancer Research. 2011 ; Vol. 71, No. 3. pp. 1071-1080.
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