Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours.
Acquired resistance to EGFR tyrosine kinase inhibitors alters the metabolism of human head and neck squamous carcinoma cells and xenograft tumours.
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DOI：
10.1038/bjc.2015.86
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发表时间：
2015-03-31
影响因子：
8.8
通讯作者：
Leach, M. O.
中科院分区：
文献类型：
--
作者：
Beloueche-Babari, M.;Box, C.;Arunan, V.;Parkes, H. G.;Valenti, M.;Brandon, A. De Haven;Jackson, L. E.;Eccles, S. A.;Leach, M. O.
对分子靶向治疗的获得性耐药性是个性化癌症医学的一个关键挑战，突出了识别复发的潜在机制和早期生物标志物的必要性，以指导后续的患者管理。在这里，我们使用人头颈部鳞状细胞癌（HNSCC）模型和核磁共振（NMR）光谱来评估EGFR酪氨酸激酶抑制剂（TKI）获得性耐药后的代谢变化，这些变化可能作为耐药的潜在代谢生物标志物。从对照（CALS）和EGFR TKI耐药（CALR）细胞中获得的NMR代谢产物谱的比较显示，在无胸腺小鼠中生长为2D单层、3D球状体或异种移植肿瘤，敏感和耐药模型之间存在许多差异。特别是，我们观察到相对于CALS单层，球状体和肿瘤，CALR中甘油磷酸胆碱（GPC）水平升高，与生长速率或环境无关。此外，在耐药球体和异种移植物中丙氨酸、天冬氨酸和肌酸+磷酸肌酸增加，仅在异种移植物中乳酸、支链氨基酸水平增加，磷酸乙醇胺水平下降。异种移植物乳酸盐积聚与葡萄糖转运蛋白GLUT-1的表达增加相关，而GPC的升高归因于GPC磷酸二酯酶的抑制。在第二个HNSCC模型中观察到甘油磷酸胆碱（GPC）和磷酸胆碱减少，这可能表明了不同的耐药机制。我们的研究揭示了代谢特征不仅与获得性EGFR TKI耐药相关，还与HNSCC模型中的生长模式、微环境和作用机制相关。这些发现值得进一步研究，作为临床疾病复发的代谢生物标志物。
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. 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. Comparison of NMR metabolite profiles obtained from control (CALS) and EGFR TKI-resistant (CALR) 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 CALR relative to CALS 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. 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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DOI：
10.1016/j.ijrobp.2010.11.022
发表时间：
2012-01-01
影响因子：
7
作者：
Jansen, Jacobus F. A.;Schoder, Heiko;Lee, Nancy Y.;Stambuk, Hilda. E.;Wang, Ya;Fury, Matthew G.;Patel, Snehal G.;Pfister, David G.;Shah, Jatin P.;Koutcher, Jason A.;Shukla-Dave, Amita
通讯作者：
Shukla-Dave, Amita
影响因子：
6.2
作者：
Gee, Harriet E.;Camps, Carme;Harris, Adrian L.
通讯作者：
Harris, Adrian L.
DOI：
10.1016/b978-0-12-397927-8.00004-x
发表时间：
2012
期刊：
Advances in pharmacology (San Diego, Calif.)
影响因子：
--
作者：
Bailey, Kate M;Wojtkowiak, Jonathan W;Hashim, Arig Ibrahim;Gillies, Robert J
通讯作者：
Gillies, Robert J
DOI：
10.1038/nrc3162
发表时间：
2011-11-17
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.9
作者：
Puig, Pierre-Emmanuel;Guilly, Marie-Noelle;Chauffert, Bruno
通讯作者：
Chauffert, Bruno