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

[11] Systematic identification of genomic markers of drug sensitivity in cancer cells [J].

Garnett, Mathew J. ;

Edelman, Elena J. ;

Heidorn, Sonja J. ;

Greenman, Chris D. ;

Dastur, Anahita ;

Lau, King Wai ;

Greninger, Patricia ;

Thompson, I. Richard ;

Luo, Xi ;

Soares, Jorge ;

Liu, Qingsong ;

Iorio, Francesco ;

Surdez, Didier ;

Chen, Li ;

Milano, Randy J. ;

Bignell, Graham R. ;

Tam, Ah T. ;

Davies, Helen ;

Stevenson, Jesse A. ;

Barthorpe, Syd ;

Lutz, Stephen R. ;

Kogera, Fiona ;

Lawrence, Karl ;

McLaren-Douglas, Anne ;

Mitropoulos, Xeni ;

Mironenko, Tatiana ;

Thi, Helen ;

Richardson, Laura ;

Zhou, Wenjun ;

Jewitt, Frances ;

Zhang, Tinghu ;

O'Brien, Patrick ;

Boisvert, Jessica L. ;

Price, Stacey ;

Hur, Wooyoung ;

Yang, Wanjuan ;

Deng, Xianming ;

Butler, Adam ;

Choi, Hwan Geun ;

Chang, JaeWon ;

Baselga, Jose ;

Stamenkovic, Ivan ;

Engelman, Jeffrey A. ;

Sharma, Sreenath V. ;

Delattre, Olivier ;

Saez-Rodriguez, Julio ;

Gray, Nathanael S. ;

Settleman, Jeffrey ;

Futreal, P. Andrew ;

Haber, Daniel A. .

NATURE, 2012, 483 (7391) :570-U87

[12] Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification [J].

Gorre, ME ;

Mohammed, M ;

Ellwood, K ;

Hsu, N ;

Paquette, R ;

Rao, PN ;

Sawyers, CL .

SCIENCE, 2001, 293 (5531) :876-880

[13] ZNF423 Is Critically Required for Retinoic Acid-induced Differentiation and Is a Marker of Neuroblastoma Outcome [J].

Huang, Sidong ;

Laoukili, Jamila ;

Epping, Mirjam T. ;

Koster, Jan ;

Holzel, Michael ;

Westerman, Bart A. ;

Nijkamp, Wouter ;

Hata, Akiko ;

Asgharzadeh, Shahab ;

Seeger, Robert C. ;

Versteeg, Rogier ;

Beijersbergen, Roderick L. ;

Bernards, Rene .

CANCER CELL, 2009, 15 (04) :328-340

[14] COT drives resistance to RAF inhibition through MAP kinase pathway reactivation [J].

Johannessen, Cory M. ;

Boehm, Jesse S. ;

Kim, So Young ;

Thomas, Sapana R. ;

Wardwell, Leslie ;

Johnson, Laura A. ;

Emery, Caroline M. ;

Stransky, Nicolas ;

Cogdill, Alexandria P. ;

Barretina, Jordi ;

Caponigro, Giordano ;

Hieronymus, Haley ;

Murray, Ryan R. ;

Salehi-Ashtiani, Kourosh ;

Hill, David E. ;

Vidal, Marc ;

Zhao, Jean J. ;

Yang, Xiaoping ;

Alkan, Ozan ;

Kim, Sungjoon ;

Harris, Jennifer L. ;

Wilson, Christopher J. ;

Myer, Vic E. ;

Finan, Peter M. ;

Root, David E. ;

Roberts, Thomas M. ;

Golub, Todd ;

Flaherty, Keith T. ;

Dummer, Reinhard ;

Weber, Barbara L. ;

Sellers, William R. ;

Schlegel, Robert ;

Wargo, Jennifer A. ;

Hahn, William C. ;

Garraway, Levi A. .

NATURE, 2010, 468 (7326) :968-U370

[15] K-ras mutations and benefit from cetuximab in advanced colorectal cancer [J].

Karapetis, Christos S. ;

Khambata-Ford, Shirin ;

Jonker, Derek J. ;

O'Callaghan, Chris J. ;

Tu, Dongsheng ;

Tebbutt, Niall C. ;

Simes, R. John ;

Chalchal, Haji ;

Shapiro, Jeremy D. ;

Robitaille, Sonia ;

Price, Timothy J. ;

Shepherd, Lois ;

Au, Heather-Jane ;

Langer, Christiane ;

Moore, Malcolm J. ;

Zalcberg, John R. .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (17) :1757-1765

[16] TGF-β sensitivity is determined by N-linked glycosylation of the type II TGF-β receptor [J].

Kim, Young-Woong ;

Park, Jinah ;

Lee, Hyun-Ju ;

Lee, So-Young ;

Kim, Seong-Jin .

BIOCHEMICAL JOURNAL, 2012, 445 :403-411

[17] Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer [J].

Kwak, Eunice L. ;

Bang, Yung-Jue ;

Camidge, D. Ross ;

Shaw, Alice T. ;

Solomon, Benjamin ;

Maki, Robert G. ;

Ou, Sai-Hong I. ;

Dezube, Bruce J. ;

Jaenne, Pasi A. ;

Costa, Daniel B. ;

Varella-Garcia, Marileila ;

Kim, Woo-Ho ;

Lynch, Thomas J. ;

Fidias, Panos ;

Stubbs, Hannah ;

Engelman, Jeffrey A. ;

Sequist, Lecia V. ;

Tan, WeiWei ;

Gandhi, Leena ;

Mino-Kenudson, Mari ;

Wei, Greg C. ;

Shreeve, S. Martin ;

Ratain, Mark J. ;

Settleman, Jeffrey ;

Christensen, James G. ;

Haber, Daniel A. ;

Wilner, Keith ;

Salgia, Ravi ;

Shapiro, Geoffrey I. ;

Clark, Jeffrey W. ;

Iafrate, A. John .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (18) :1693-1703

[18] EMT is the dominant program in human colon cancer [J].

Loboda, Andre ;

Nebozhyn, Michael V. ;

Watters, James W. ;

Buser, Carolyne A. ;

Shaw, Peter Martin ;

Huang, Pearl S. ;

Van't Veer, Laura ;

Tollenaar, Rob A. E. M. ;

Jackson, David B. ;

Agrawal, Deepak ;

Dai, Hongyue ;

Yeatman, Timothy J. .

BMC MEDICAL GENOMICS, 2011, 4

[19] Gefitinib or Chemotherapy for Non-Small-Cell Lung Cancer with Mutated EGFR. [J].

Maemondo, Makoto ;

Inoue, Akira ;

Kobayashi, Kunihiko ;

Sugawara, Shunichi ;

Oizumi, Satoshi ;

Isobe, Hiroshi ;

Gemma, Akihiko ;

Harada, Masao ;

Yoshizawa, Hirohisa ;

Kinoshita, Ichiro ;

Fujita, Yuka ;

Okinaga, Shoji ;

Hirano, Haruto ;

Yoshimori, Kozo ;

Harada, Toshiyuki ;

Ogura, Takashi ;

Ando, Masahiro ;

Miyazawa, Hitoshi ;

Tanaka, Tomoaki ;

Saijo, Yasuo ;

Hagiwara, Koichi ;

Morita, Satoshi ;

Nukiwa, Toshihiro .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (25) :2380-2388

[20] MED12, the Mediator Complex Subunit 12 Gene, Is Mutated at High Frequency in Uterine Leiomyomas [J].

Makinen, Netta ;

Mehine, Miika ;

Tolvanen, Jaana ;

Kaasinen, Eevi ;

Li, Yilong ;

Lehtonen, Heli J. ;

Gentile, Massimiliano ;

Yan, Jian ;

Enge, Martin ;

Taipale, Minna ;

Aavikko, Mervi ;

Katainen, Riku ;

Virolainen, Elina ;

Bohling, Tom ;

Koski, Taru A. ;

Launonen, Virpi ;

Sjoberg, Jari ;

Taipale, Jussi ;

Vahteristo, Pia ;

Aaltonen, Lauri A. .

SCIENCE, 2011, 334 (6053) :252-255

← 1 2 3 4 →