Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways
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David W. Greening1,*, Sze Ting Lee2,3,4,*, Hong Ji1, Richard J. Simpson1, Angela Rigopoulos3,4, Carmel Murone3,4, Catherine Fang3,4, Sylvia Gong2, Graeme O’Keefe2,3,4 and Andrew M. Scott2,3,4,*
1 Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
2 Department of Molecular Imaging and Therapy, University of Melbourne, Austin Hospital, Melbourne, Australia
3 Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia
4 School of Cancer Medicine, La Trobe University, Melbourne, Australia
* These authors have contributed equally to this work
Andrew M. Scott, email:
David W. Greening, email:
Keywords: cetuximab, bevacizumab, cancer therapeutics, metabolism, hypoxia
Received: August 17, 2015 Accepted: September 18, 2015 Published: October 26, 2015
Angiogenesis and epidermal growth factor receptor (EGFR) inhibition has been shown to have anti-tumour efficacy, and enhance the therapeutic effects of cytotoxic chemotherapy in metastatic colorectal cancer. The interplay of signalling alterations and changes in metabolism and hypoxia in tumours following anti-VEGF and anti-EGFR treatment is not well understood. We aimed to explore the pharmacodynamics of cetuximab and bevacizumab treatment in human colon carcinoma tumour cells in vitro and xenograft models through proteomic profiling, molecular imaging of metabolism and hypoxia, and evaluation of therapy-induced changes in tumour cells and the tumour microenvironment. Both cetuximab and bevacizumab inhibited tumour growth in vivo, and this effect was associated with selectively perturbed glucose metabolism and reduced hypoxic volumes based on PET/MRI imaging. Global proteomic profiling of xenograft tumours (in presence of cetuximab, bevacizumab, and combination treatments) revealed alterations in proteins involved in glucose, lipid and fatty acid metabolism (e.g., GPD2, ATP5B, STAT3, FASN), as well as hypoxic regulators and vasculogenesis (e.g., ATP5B, THBS1, HSPG2). These findings correlated with western immunoblotting (xenograft lysates) and histological examination by immunohistochemistry. These results define important mechanistic insight into the dynamic changes in metabolic and hypoxic response pathways in colorectal tumours following treatment with cetuximab and bevacizumab, and highlight the ability of these therapies to selectively impact on tumour cells and extracellular microenvironment.
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