Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells

被引：144

作者：

Baenke, Franziska ^{[1
]}

Chaneton, Barbara ^{[2
]}

Smith, Matthew ^{[1
]}

Van Den Broek, Niels ^{[2
]}

Hogan, Kate ^{[1
]}

Tang, Haoran ^{[1
]}

Viros, Amaya ^{[1
]}

Martin, Matthew ^{[1
]}

Galbraith, Laura ^{[2
]}

Girotti, Maria R. ^{[1
]}

Dhomen, Nathalie ^{[1
]}

Gottlieb, Eyal ^{[2
]}

Marais, Richard ^{[1
]}

机构：

[1] Univ Manchester, Canc Res UK Manchester Inst, Mol Oncol Lab, Wilmslow Rd, Manchester M20 4BX, Lancs, England

[2] Canc Res UK Beatson Inst, Canc Metab Res Unit, Switchback Rd, Glasgow G61 1BD, Lanark, Scotland

来源：

MOLECULAR ONCOLOGY | 2016年 / 10卷 / 01期

基金：

英国惠康基金;

关键词：

BRAF; Resistance; Melanoma; Metabolism; Glutaminolysis; GLUCOSE-METABOLISM; DRIVEN RESISTANCE; OXIDATIVE STRESS; RAF INHIBITORS; BREAST-CANCER; PATHWAY; GROWTH; MUTANT; IMMUNOTHERAPIES; BRAF(V600E);

D O I：

10.1016/j.molonc.2015.08.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first line setting. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.

引用

页码：73 / 84

页数：12

共 46 条

[1]

Cancer Cell Metabolism: One Hallmark, Many Faces [J].

Cantor, Jason R. ;

Sabatini, David M. .

CANCER DISCOVERY, 2012, 2 (10) :881-898

[2]

Serine is a natural ligand and allosteric activator of pyruvate kinase M2 [J].

Chaneton, Barbara ;

Hillmann, Petra ;

Zheng, Liang ;

Martin, Agnes C. L. ;

Maddocks, Oliver D. K. ;

Chokkathukalam, Achuthanunni ;

Coyle, Joseph E. ;

Jankevics, Andris ;

Holding, Finn P. ;

Vousden, Karen H. ;

Frezza, Christian ;

O'Reilly, Marc ;

Gottlieb, Eyal .

NATURE, 2012, 491 (7424) :458-+

[3]

Mitochondrial oxidative stress is the achille's heel of melanoma cells resistant to Braf-mutant inhibitor [J].

Corazao-Rozas, Paola ;

Guerreschi, Pierre ;

Jendoubi, Manel ;

Andre, Fanny ;

Jonneaux, Aurelie ;

Scalbert, Camille ;

Garcon, Guillaume ;

Malet-Martino, Myriam ;

Balayssac, Stephane ;

Rocchi, Stephane ;

Savina, Ariel ;

Formstecher, Pierre ;

Mortier, Laurent ;

Kluza, Jerome ;

Marchetti, Philippe .

ONCOTARGET, 2013, 4 (11) :1986-1998

[4]

Cancer-associated IDH1 mutations produce 2-hydroxyglutarate [J].

Dang, Lenny ;

White, David W. ;

Gross, Stefan ;

Bennett, Bryson D. ;

Bittinger, Mark A. ;

Driggers, Edward M. ;

Fantin, Valeria R. ;

Jang, Hyun Gyung ;

Jin, Shengfang ;

Keenan, Marie C. ;

Marks, Kevin M. ;

Prins, Robert M. ;

Ward, Patrick S. ;

Yen, Katharine E. ;

Liau, Linda M. ;

Rabinowitz, Joshua D. ;

Cantley, Lewis C. ;

Thompson, Craig B. ;

Heiden, Matthew G. Vander ;

Su, Shinsan M. .

NATURE, 2009, 462 (7274) :739-U52

[5]

Mutations of the BRAF gene in human cancer [J].

Davies, H ;

Bignell, GR ;

Cox, C ;

Stephens, P ;

Edkins, S ;

Clegg, S ;

Teague, J ;

Woffendin, H ;

Garnett, MJ ;

Bottomley, W ;

Davis, N ;

Dicks, N ;

Ewing, R ;

Floyd, Y ;

Gray, K ;

Hall, S ;

Hawes, R ;

Hughes, J ;

Kosmidou, V ;

Menzies, A ;

Mould, C ;

Parker, A ;

Stevens, C ;

Watt, S ;

Hooper, S ;

Wilson, R ;

Jayatilake, H ;

Gusterson, BA ;

Cooper, C ;

Shipley, J ;

Hargrave, D ;

Pritchard-Jones, K ;

Maitland, N ;

Chenevix-Trench, G ;

Riggins, GJ ;

Bigner, DD ;

Palmieri, G ;

Cossu, A ;

Flanagan, A ;

Nicholson, A ;

Ho, JWC ;

Leung, SY ;

Yuen, ST ;

Weber, BL ;

Siegler, HF ;

Darrow, TL ;

Paterson, H ;

Marais, R ;

Marshall, CJ ;

Wooster, R .

NATURE, 2002, 417 (6892) :949-954

[6]

BRAF Signaling and Targeted Therapies in Melanoma [J].

Dhomen, Nathalie ;

Marais, Richard .

HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA, 2009, 23 (03) :529-+

[7]

Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase [J].

Frezza, Christian ;

Zheng, Liang ;

Folger, Ori ;

Rajagopalan, Kartik N. ;

MacKenzie, Elaine D. ;

Jerby, Livnat ;

Micaroni, Massimo ;

Chaneton, Barbara ;

Adam, Julie ;

Hedley, Ann ;

Kalna, Gabriela ;

Tomlinson, Ian P. M. ;

Pollard, Patrick J. ;

Watson, Dave G. ;

Deberardinis, Ralph J. ;

Shlomi, Tomer ;

Ruppin, Eytan ;

Gottlieb, Eyal .

NATURE, 2011, 477 (7363) :225-U132

[8]

Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma [J].

Girotti, Maria R. ;

Pedersen, Malin ;

Sanchez-Laorden, Berta ;

Viros, Amaya ;

Turajlic, Samra ;

Niculescu-Duvaz, Dan ;

Zambon, Alfonso ;

Sinclair, John ;

Hayes, Andrew ;

Gore, Martin ;

Lorigan, Paul ;

Springer, Caroline ;

Larkin, James ;

Jorgensen, Claus ;

Marais, Richard .

CANCER DISCOVERY, 2013, 3 (02) :158-167

[9]

No longer an untreatable disease: How targeted and immunotherapies have changed the management of melanoma patients [J].

Girotti, Maria Romina ;

Saturno, Grazia ;

Lorigan, Paul ;

Marais, Richard .

MOLECULAR ONCOLOGY, 2014, 8 (06) :1140-1158

[10]

Essential amino acids and glutamine regulate induction of mitochondrial elongation during autophagy [J].

Gomes, Ligia C. ;

Di Benedetto, Giulietta ;

Scorrano, Luca .

CELL CYCLE, 2011, 10 (16) :2635-2639

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