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Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours.

Beloueche-Babari M, Box C, Arunan V, Parkes HG, Valenti M, De Haven Brandon A, Jackson LE, Eccles SA, Leach MO - Br. J. Cancer (2015)

Bottom Line: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management.Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models.These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK.

ABSTRACT

Background: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management.

Methods: Here we use human head and neck squamous cell carcinoma (HNSCC) models and nuclear magnetic resonance (NMR) spectroscopy to assess the metabolic changes that follow acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), and which could serve as potential metabolic biomarkers of drug resistance.

Results: Comparison of NMR metabolite profiles obtained from control (CAL(S)) and EGFR TKI-resistant (CAL(R)) cells grown as 2D monolayers, 3D spheroids or xenograft tumours in athymic mice revealed a number of differences between the sensitive and drug-resistant models. In particular, we observed elevated levels of glycerophosphocholine (GPC) in CAL(R) relative to CAL(S) monolayers, spheroids and tumours, independent of the growth rate or environment. In addition, there was an increase in alanine, aspartate and creatine+phosphocreatine in resistant spheroids and xenografts, and increased levels of lactate, branched-chain amino acids and a fall in phosphoethanolamine only in xenografts. The xenograft lactate build-up was associated with an increased expression of the glucose transporter GLUT-1, whereas the rise in GPC was attributed to inhibition of GPC phosphodiesterase. Reduced glycerophosphocholine (GPC) and phosphocholine were observed in a second HNSCC model probably indicative of a different drug resistance mechanism.

Conclusions: Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models. These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic.

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Related in: MedlinePlus

GLUT-1 expression in CALS and CALR tumour models. Western blots showing an elevated GLUT-1 protein expression in CALR relative to CALS xenograft tumours but not in 2D monolayers or 3D spheroids. The individual lanes in the tumour blot represent samples from individual xenografts.
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fig3: GLUT-1 expression in CALS and CALR tumour models. Western blots showing an elevated GLUT-1 protein expression in CALR relative to CALS xenograft tumours but not in 2D monolayers or 3D spheroids. The individual lanes in the tumour blot represent samples from individual xenografts.

Mentions: The increased lactate observed in tumours but not 2D or 3D in vitro cultures could suggest a shift towards glycolytic metabolism (also known as the Warburg effect) in vivo. To investigate this possibility we assessed the protein expression levels of the glucose transporter GLUT-1. Our data indicate that CALR have upregulated GLUT-1 expression compared with CALS tumours, consistent with an increased Warburg effect. Interestingly, this difference was not observed in cells grown as 2D monolayers or 3D spheroids (Figure 3), where lactate levels were unchanged.


Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours.

Beloueche-Babari M, Box C, Arunan V, Parkes HG, Valenti M, De Haven Brandon A, Jackson LE, Eccles SA, Leach MO - Br. J. Cancer (2015)

GLUT-1 expression in CALS and CALR tumour models. Western blots showing an elevated GLUT-1 protein expression in CALR relative to CALS xenograft tumours but not in 2D monolayers or 3D spheroids. The individual lanes in the tumour blot represent samples from individual xenografts.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385966&req=5

fig3: GLUT-1 expression in CALS and CALR tumour models. Western blots showing an elevated GLUT-1 protein expression in CALR relative to CALS xenograft tumours but not in 2D monolayers or 3D spheroids. The individual lanes in the tumour blot represent samples from individual xenografts.
Mentions: The increased lactate observed in tumours but not 2D or 3D in vitro cultures could suggest a shift towards glycolytic metabolism (also known as the Warburg effect) in vivo. To investigate this possibility we assessed the protein expression levels of the glucose transporter GLUT-1. Our data indicate that CALR have upregulated GLUT-1 expression compared with CALS tumours, consistent with an increased Warburg effect. Interestingly, this difference was not observed in cells grown as 2D monolayers or 3D spheroids (Figure 3), where lactate levels were unchanged.

Bottom Line: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management.Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models.These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic.

View Article: PubMed Central - PubMed

Affiliation: Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK.

ABSTRACT

Background: Acquired resistance to molecularly targeted therapeutics is a key challenge in personalised cancer medicine, highlighting the need for identifying the underlying mechanisms and early biomarkers of relapse, in order to guide subsequent patient management.

Methods: Here we use human head and neck squamous cell carcinoma (HNSCC) models and nuclear magnetic resonance (NMR) spectroscopy to assess the metabolic changes that follow acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), and which could serve as potential metabolic biomarkers of drug resistance.

Results: Comparison of NMR metabolite profiles obtained from control (CAL(S)) and EGFR TKI-resistant (CAL(R)) cells grown as 2D monolayers, 3D spheroids or xenograft tumours in athymic mice revealed a number of differences between the sensitive and drug-resistant models. In particular, we observed elevated levels of glycerophosphocholine (GPC) in CAL(R) relative to CAL(S) monolayers, spheroids and tumours, independent of the growth rate or environment. In addition, there was an increase in alanine, aspartate and creatine+phosphocreatine in resistant spheroids and xenografts, and increased levels of lactate, branched-chain amino acids and a fall in phosphoethanolamine only in xenografts. The xenograft lactate build-up was associated with an increased expression of the glucose transporter GLUT-1, whereas the rise in GPC was attributed to inhibition of GPC phosphodiesterase. Reduced glycerophosphocholine (GPC) and phosphocholine were observed in a second HNSCC model probably indicative of a different drug resistance mechanism.

Conclusions: Our studies reveal metabolic signatures associated not only with acquired EGFR TKI resistance but also growth pattern, microenvironment and contributing mechanisms in HNSCC models. These findings warrant further investigation as metabolic biomarkers of disease relapse in the clinic.

Show MeSH
Related in: MedlinePlus