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Title: Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways
Austin Authors: Greening, David W;Lee, Sze Ting ;Ji, Hong;Simpson, Richard J;Rigopoulos, Angela;Murone, Carmel ;Fang, Catherine;Gong, Sylvia J;O’Keefe, Graeme J;Scott, Andrew M 
Affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
Department of Molecular Imaging and Therapy, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia
Issue Date: 10-Nov-2015 2015-10-26
Publication information: Oncotarget 2015; 6(35): 38166-38180
Abstract: 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.
DOI: 10.18632/oncotarget.6241
ORCID: 0000-0002-6656-295X
PubMed URL:
Type: Journal Article
Subjects: Bevacizumab
Cancer therapeutics
Appears in Collections:Journal articles

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