Molecular profiling of cetuximab and bevacizumab treatment of colorectal tumours reveals perturbations in metabolic and hypoxic response pathways.

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