MED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling

被引：380

作者：

Huang, Sidong ^{[1
,2
]}

Hoelzel, Michael ^{[1
,2
]}

Knijnenburg, Theo ^{[1
,2
]}

Schlicker, Andreas ^{[1
,2
]}

Roepman, Paul ^{[4
,5
]}

McDermott, Ultan ^{[6
]}

Garnett, Mathew ^{[6
]}

Grernrum, Wipawadee ^{[1
,2
]}

Sun, Chong ^{[1
,2
]}

Prahallad, Anirudh ^{[1
,2
]}

Groenendijk, Floris H. ^{[1
,2
]}

Mittempergher, Lorenza ^{[1
,2
]}

Nijkamp, Wouter ^{[1
,2
]}

Neefjes, Jacques ^{[3
]}

Salazar, Ramon ^{[7
]}

ten Dijke, Peter ^{[8
]}

Uramoto, Hidetaka ^{[9
]}

Tanaka, Fumihiro ^{[9
]}

Beijersbergen, Roderick L. ^{[1
,2
]}

Wessels, Lodewyk F. A. ^{[1
,2
]}

Bernards, Rene ^{[1
,2
,4
,5
]}

机构：

[1] Netherlands Canc Inst, Canc Genom Ctr, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands

[2] Netherlands Canc Inst, Canc Syst Biol Ctr, NL-1066 CX Amsterdam, Netherlands

[3] Netherlands Canc Inst, Div Cell Biol, NL-1066 CX Amsterdam, Netherlands

[4] Agendia Inc, Irvine, CA 92618 USA

[5] Agendia NV, NL-1098 XH Amsterdam, Netherlands

[6] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[7] Inst Catala Oncol IDIBELL, Lhospitalet De Llobregat 08908, Spain

[8] Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands

[9] Univ Occupat & Environm Hlth, Dept Surg 2, Sch Med, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan

来源：

CELL | 2012年 / 151卷 / 05期

基金：

欧洲研究理事会;

关键词：

ANAPLASTIC LYMPHOMA KINASE; CELL LUNG-CANCER; COLORECTAL-CANCER; RESISTANCE; MUTATIONS; SENSITIVITY; INHIBITION; PATHWAY; THERAPY; SCREEN;

D O I：

10.1016/j.cell.2012.10.035

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：

Inhibitors of the ALK and EGF receptor tyrosine kinases provoke dramatic but short-lived responses in lung cancers harboring EML4-ALK translocations or activating mutations of EGFR, respectively. We used a large-scale RNAi screen to identify MED12, a component of the transcriptional MEDIATOR complex that is mutated in cancers, as a determinant of response to ALK and EGFR inhibitors. MED12 is in part cytoplasmic where it negatively regulates TGF-beta R2 through physical interaction. MED12 suppression therefore results in activation of TGF-beta R signaling, which is both necessary and sufficient for drug resistance. TGF-beta signaling causes MEK/ERK activation, and consequently MED12 suppression also confers resistance to MEK and BRAF inhibitors in other cancers. MED12 loss induces an EMT-like phenotype, which is associated with chemotherapy resistance in colon cancer patients and to gefitinib in lung cancer. Inhibition of TGF-beta R signaling restores drug responsiveness in MED12(KD) cells, suggesting a strategy to treat drug-resistant tumors that have lost MED12.

引用

页码：937 / 950

页数：14

共 31 条

[1] Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer [J].

Barbieri, Christopher E. ;

Baca, Sylvan C. ;

Lawrence, Michael S. ;

Demichelis, Francesca ;

Blattner, Mirjam ;

Theurillat, Jean-Philippe ;

White, Thomas A. ;

Stojanov, Petar ;

Van Allen, Eliezer ;

Stransky, Nicolas ;

Nickerson, Elizabeth ;

Chae, Sung-Suk ;

Boysen, Gunther ;

Auclair, Daniel ;

Onofrio, Robert C. ;

Park, Kyung ;

Kitabayashi, Naoki ;

MacDonald, Theresa Y. ;

Sheikh, Karen ;

Vuong, Terry ;

Guiducci, Candace ;

Cibulskis, Kristian ;

Sivachenko, Andrey ;

Carter, Scott L. ;

Saksena, Gordon ;

Voet, Douglas ;

Hussain, Wasay M. ;

Ramos, Alex H. ;

Winckler, Wendy ;

Redman, Michelle C. ;

Ardlie, Kristin ;

Tewari, Ashutosh K. ;

Mosquera, Juan Miguel ;

Rupp, Niels ;

Wild, Peter J. ;

Moch, Holger ;

Morrissey, Colm ;

Nelson, Peter S. ;

Kantoff, Philip W. ;

Gabriel, Stacey B. ;

Golub, Todd R. ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad ;

Rubin, Mark A. ;

Garraway, Levi A. .

NATURE GENETICS, 2012, 44 (06) :685-U107

[2] A large-scale RNAi screen in human cells identifies new components of the p53 pathway [J].

Berns, K ;

Hijmans, EM ;

Mullenders, J ;

Brummelkamp, TR ;

Velds, A ;

Heimerikx, M ;

Kerkhoven, RM ;

Madiredjo, M ;

Nijkamp, W ;

Weigelt, B ;

Agami, R ;

Ge, W ;

Cavet, G ;

Linsley, PS ;

Beijersbergen, RL ;

Bernards, R .

NATURE, 2004, 428 (6981) :431-437

[3] A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer [J].

Berns, Katrien ;

Horlings, Hugo M. ;

Hennessy, Bryan T. ;

Madiredjo, Mandy ;

Hijmans, E. Marielle ;

Beelen, Karin ;

Linn, Sabine C. ;

Gonzalez-Angulo, Ana Maria ;

Stemke-Hale, Katherine ;

Hauptmann, Michael ;

Beijersbergen, Roderick L. ;

Mills, Gordon B. ;

de Vijver, Marc J. van ;

Bernards, Rene .

CANCER CELL, 2007, 12 (04) :395-402

[4] An shRNA barcode screen provides insight into cancer cell vulnerability to MDM2 inhibitors [J].

Brummelkamp, TR ;

Fabius, AWM ;

Mullenders, J ;

Madiredjo, M ;

Velds, A ;

Kerkhoven, RM ;

Bernards, R ;

Beijersbergen, RL .

NATURE CHEMICAL BIOLOGY, 2006, 2 (04) :202-206

[5] Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation [J].

Chapman, Paul B. ;

Hauschild, Axel ;

Robert, Caroline ;

Haanen, John B. ;

Ascierto, Paolo ;

Larkin, James ;

Dummer, Reinhard ;

Garbe, Claus ;

Testori, Alessandro ;

Maio, Michele ;

Hogg, David ;

Lorigan, Paul ;

Lebbe, Celeste ;

Jouary, Thomas ;

Schadendorf, Dirk ;

Ribas, Antoni ;

O'Day, Steven J. ;

Sosman, Jeffrey A. ;

Kirkwood, John M. ;

Eggermont, Alexander M. M. ;

Dreno, Brigitte ;

Nolop, Keith ;

Li, Jiang ;

Nelson, Betty ;

Hou, Jeannie ;

Lee, Richard J. ;

Flaherty, Keith T. ;

McArthur, Grant A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 364 (26) :2507-2516

[6] EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors [J].

Choi, Young Lim ;

Soda, Manabu ;

Yamashita, Yoshihiro ;

Ueno, Toshihide ;

Takashima, Junpei ;

Nakajima, Takahiro ;

Yatabe, Yasushi ;

Takeuchi, Kengo ;

Hamada, Toru ;

Haruta, Hidenori ;

Ishikawa, Yuichi ;

Kimura, Hideki ;

Mitsudomi, Tetsuya ;

Tanio, Yoshiro ;

Mano, Hiroyuki .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (18) :1734-1739

[7] The mammalian Mediator complex and its role in transcriptional regulation [J].

Conaway, RC ;

Sato, S ;

Tomomori-Sato, C ;

Yao, TT ;

Conaway, JW .

TRENDS IN BIOCHEMICAL SCIENCES, 2005, 30 (05) :250-255

[8] CDK8 is a colorectal cancer oncogene that regulates β-catenin activity [J].

Firestein, Ron ;

Bass, Adam J. ;

Kim, So Young ;

Dunn, Ian F. ;

Silver, Serena J. ;

Guney, Isil ;

Freed, Ellen ;

Ligon, Azra H. ;

Vena, Natalie ;

Ogino, Shuji ;

Chheda, Milan G. ;

Tamayo, Pablo ;

Finn, Stephen ;

Shrestha, Yashaswi ;

Boehm, Jesse S. ;

Jain, Supriya ;

Bojarski, Emeric ;

Mermel, Craig ;

Barretina, Jordi ;

Chan, Jennifer A. ;

Baselga, Jose ;

Tabernero, Josep ;

Root, David E. ;

Fuchs, Charles S. ;

Loda, Massimo ;

Shivdasani, Ramesh A. ;

Meyerson, Matthew ;

Hahn, William C. .

NATURE, 2008, 455 (7212) :547-U60

[9] COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer [J].

Forbes, Simon A. ;

Tang, Gurpreet ;

Bindal, Nidhi ;

Bamford, Sally ;

Dawson, Elisabeth ;

Cole, Charlotte ;

Kok, Chai Yin ;

Jia, Mingming ;

Ewing, Rebecca ;

Menzies, Andrew ;

Teague, Jon W. ;

Stratton, Michael R. ;

Futreal, P. Andrew .

NUCLEIC ACIDS RESEARCH, 2010, 38 :D652-D657

[10] Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells [J].

Fuchs, Bryan C. ;

Fujii, Tsutomu ;

Dorfman, Jon D. ;

Goodwin, Jonathan M. ;

Zhu, Andrew X. ;

Lanuti, Michael ;

Tanabe, Kenneth K. .

CANCER RESEARCH, 2008, 68 (07) :2391-2399

← 1 2 3 4 →