The transcription cofactor c-JUN mediates phenotype switching and BRAF inhibitor resistance in melanoma

被引:99
作者
Ramsdale, Rachel [1 ,2 ]
Jorissen, Robert N. [3 ,4 ]
Li, Frederic Z. [1 ,2 ,5 ]
Al-Obaidi, Sheren [1 ,2 ]
Ward, Teresa [1 ,2 ]
Sheppard, Karen E. [1 ,2 ,6 ]
Bukczynska, Patricia E. [7 ,8 ]
Young, Richard J. [7 ,8 ]
Boyle, Samantha E. [8 ,9 ,10 ]
Shackleton, Mark [8 ,9 ,10 ]
Bollag, Gideon [11 ]
Long, Georgina V. [12 ,13 ]
Tulchinsky, Eugene [14 ]
Rizos, Helen [12 ,15 ]
Pearson, Richard B. [2 ,5 ,6 ,16 ]
McArthur, Grant A. [1 ,2 ,5 ,8 ]
Dhillon, Amardeep S. [2 ,5 ,10 ]
Ferrao, Petranel T. [1 ,2 ,5 ,8 ,10 ]
机构
[1] Peter MacCallum Canc Ctr, Mol Oncol Lab, East Melbourne, Vic 3002, Australia
[2] Peter MacCallum Canc Ctr, Oncogen Signalling & Growth Control Program, East Melbourne, Vic 3002, Australia
[3] Walter & Eliza Hall Inst Med Res, Syst Biol & Personalised Med Div, Parkville, Vic 3052, Australia
[4] Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Med Biol, Melbourne, Vic 3010, Australia
[5] Univ Melbourne, Fac Med Dent & Hlth Sci, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3010, Australia
[6] Univ Melbourne, Fac Med Dent & Hlth Sci, Dept Biochem & Mol Biol, Melbourne, Vic 3010, Australia
[7] Peter MacCallum Canc Ctr, Mol Therapeut & Biomarkers Lab, East Melbourne, Vic 3002, Australia
[8] Peter MacCallum Canc Ctr, Canc Therapeut Program, East Melbourne, Vic 3002, Australia
[9] Peter MacCallum Canc Ctr, Canc Dev & Treatment Lab, East Melbourne, Vic 3002, Australia
[10] Univ Melbourne, Dept Pathol, Fac Med Dent & Hlth Sci, Melbourne, Vic 3010, Australia
[11] Plexxikon Inc, Berkeley, CA 94710 USA
[12] Melanoma Inst Australia, Sydney, NSW 2060, Australia
[13] Univ Sydney, Sydney, NSW 2006, Australia
[14] Univ Leicester, Dept Canc Studies & Mol Med, Leicester LE2 7LX, Leics, England
[15] Macquarie Univ, Fac Med & Hlth Sci, Dept Biomed Sci, Sydney, NSW 2109, Australia
[16] Peter MacCallum Canc Ctr, Canc Signalling Lab, East Melbourne, Vic 3002, Australia
基金
英国医学研究理事会;
关键词
ADAPTIVE RESISTANCE; MESENCHYMAL TRANSITION; IMPROVED SURVIVAL; MEK INHIBITION; RAF INHIBITORS; STEM-CELLS; E-CADHERIN; EXPRESSION; CANCER; KINASE;
D O I
10.1126/scisignal.aab1111
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Most patients with BRAF-mutant metastatic melanoma display remarkable but incomplete and short-lived responses to inhibitors of the BRAF kinase or the mitogen-activated protein kinase kinase (MEK), collectively BRAF/MEK inhibitors. We found that inherent resistance to these agents in BRAF(V600)-mutant melanoma cell lines was associated with high abundance of c-JUN and characteristics of a mesenchymal-like phenotype. Early drug adaptation in drug-sensitive cell lines grown in culture or as xenografts, and in patient samples during therapy, was consistently characterized by down-regulation of SPROUTY4 (a negative feedback regulator of receptor tyrosine kinases and the BRAF-MEK signaling pathway), increased expression of JUN and reduced expression of LEF1. This coincided with a switch in phenotype that resembled an epithelial-mesenchymal transition (EMT). In cultured cells, these BRAF inhibitor-induced changes were reversed upon removal of the drug. Knockdown of SPROUTY4 was sufficient to increase the abundance of c-JUN in the absence of drug treatment. Overexpressing c-JUN in drug-naive melanoma cells induced similar EMT-like phenotypic changes to BRAF inhibitor treatment, whereas knocking down JUN abrogated the BRAF inhibitor-induced early adaptive changes associated with resistance and enhanced cell death. Combining the BRAF inhibitor with an inhibitor of c-JUN amino-terminal kinase (JNK) reduced c-JUN phosphorylation, decreased cell migration, and increased cell death in melanoma cells. Gene expression data from a panel of melanoma cell lines and a patient cohort showed that JUN expression correlated with a mesenchymal gene signature, implicating c-JUN as a key mediator of the mesenchymal-like phenotype associated with drug resistance.
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页数:13
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