Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours.
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.
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.
M
M
Beloueche-Babari
Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
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C
Box
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.
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V
Arunan
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.
H G
HG
Parkes
Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
M
M
Valenti
Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
A
A
De Haven Brandon
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.
L E
LE
Jackson
Division of Cancer Therapeutics, The Institute of Cancer Research, London SM2 5NG, UK.
S A
SA
Eccles
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.
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MO
Leach
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors