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

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.

SUBMITTER: Greening DW

PROVIDER: S-EPMC4741991 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Greening David W DW Lee Sze Ting ST Ji Hong H Simpson Richard J RJ Rigopoulos Angela A Murone Carmel C Fang Catherine C Gong Sylvia S O'Keefe Graeme G Scott Andrew M AM

Oncotarget 20151101 35

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 xeno ...[more]

PMID: 26517691

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Project description:BackgroundWe analyzed the influence of 8 germinal polymorphisms of candidate genes potentially related to EGFR signalling (EGFR, EGF, CCND1) or antibody-directed cell cytotoxicity (FCGR2A and FCGR3A) on outcome of colorectal cancer (CRC) patients receiving cetuximab-based therapy.MethodsFifty-eight advanced CRC patients treated with cetuximab-irinotecan salvage therapy between 2001 and 2007 were analyzed (mean age 60; 50 PS 0-1). The following polymorphisms were analyzed on blood DNA: EGFR (CA repeats in intron 1, -216 G > T, -191C > A, R497K), EGF (A61G), CCND1 (A870G), FCGR2A (R131H), FCGR3A (F158V). Statistical analyses were conducted on the total population and on patients with wt KRas tumors. All SNPs were considered as ternary variables (wt/wt vs wt/mut vs mut/mut), with the exception of -191C > A EGFR polymorphism (AA patient merged with CA patients).ResultsAnalysis of skin toxicity as a function of EGFR intron 1 polymorphism showed a tendency for higher toxicity in patients with a low number of CA-repeats (p = 0.058). CCND1 A870G polymorphism was significantly related to clinical response, both in the entire population and in KRas wt patients, with the G allele being associated with a lack of response. In wt KRas patients, time to progression (TTP) was significantly related to EGFR -191C > A polymorphism with a longer TTP in CC patients as compared to others, and to CCND1 A870G polymorphism with the G allele being associated with a shorter TTP; a multivariate analysis including these two polymorphisms only retained CCND1 polymorphism. Overall survival was significantly related to CCND1 polymorphism with a shorter survival in patients bearing the G allele, and to FCGR3A F158V polymorphism with a shorter survival in VV patients (in the entire population and in KRas wt patients). FCGR3A F158V and CCND1 A870G polymorphisms were significant independent predictors of overall survival.ConclusionsPresent original data obtained in wt KRas patients corresponding to the current cetuximab-treated population clearly suggest that CCND1 A870G polymorphism may be used as an additional marker for predicting cetuximab efficacy, TTP and overall survival. In addition, FCGR3A F158V polymorphism was a significant independent predictor of overall survival.

Dataset Information

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

Publications

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

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