c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma

被引：249

作者：

Blasco, Rafael B.

Francoz, Sarah

Santamaria, David

Canamero, Marta ^{[1
]}

Dubus, Pierre ^{[2
]}

Charron, Jean ^{[3
]}

Baccarini, Manuela ^{[4
]}

Barbacid, Mariano ^{[1
]}

机构：

[1] CNIO, Biotechnol Programmes, E-28029 Madrid, Spain

[2] Univ Bordeaux, EA2406, F-33076 Bordeaux, France

[3] Univ Laval, CRCHUQ, Hotel Dieu Quebec, Ctr Rech Cancerol, Quebec City, PQ G1R 2J6, Canada

[4] Univ Vienna, Ctr Mol Biol, Max F Perutz Labs, A-1030 Vienna, Austria

来源：

CANCER CELL | 2011年 / 19卷 / 05期

基金：

欧洲研究理事会; 加拿大健康研究院;

关键词：

ORAL MEK INHIBITOR; PHASE-II; TUMOR PROGRESSION; MAP KINASE; CANCER; BRAF; ERK; REVEALS; PATHWAY; GROWTH;

D O I：

10.1016/j.ccr.2011.04.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.

引用

页码：652 / 663

页数：12

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[1] Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].

Barbie, David A. ;

Tamayo, Pablo ;

Boehm, Jesse S. ;

Kim, So Young ;

Moody, Susan E. ;

Dunn, Ian F. ;

Schinzel, Anna C. ;

Sandy, Peter ;

Meylan, Etienne ;

Scholl, Claudia ;

Froehling, Stefan ;

Chan, Edmond M. ;

Sos, Martin L. ;

Michel, Kathrin ;

Mermel, Craig ;

Silver, Serena J. ;

Weir, Barbara A. ;

Reiling, Jan H. ;

Sheng, Qing ;

Gupta, Piyush B. ;

Wadlow, Raymond C. ;

Le, Hanh ;

Hoersch, Sebastian ;

Wittner, Ben S. ;

Ramaswamy, Sridhar ;

Livingston, David M. ;

Sabatini, David M. ;

Meyerson, Matthew ;

Thomas, Roman K. ;

Lander, Eric S. ;

Mesirov, Jill P. ;

Root, David E. ;

Gilliland, D. Gary ;

Jacks, Tyler ;

Hahn, William C. .

NATURE, 2009, 462 (7269) :108-U122

[2] Mek2 is dispensable for mouse growth and development [J].

Bélanger, LF ;

Roy, S ;

Tremblay, M ;

Brott, B ;

Steff, AM ;

Mourad, W ;

Hugo, P ;

Erikson, R ;

Charron, J .

MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (14) :4778-4787

[3] Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis [J].

Bissonauth, Vickram ;

Roy, Sophie ;

Gravel, Mathieu ;

Guillemette, Stephanie ;

Charron, Jean .

DEVELOPMENT, 2006, 133 (17) :3429-3440

[4] Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma [J].

Bollag, Gideon ;

Hirth, Peter ;

Tsai, James ;

Zhang, Jiazhong ;

Ibrahim, Prabha N. ;

Cho, Hanna ;

Spevak, Wayne ;

Zhang, Chao ;

Zhang, Ying ;

Habets, Gaston ;

Burton, ElizabethA. ;

Wong, Bernice ;

Tsang, Garson ;

West, Brian L. ;

Powell, Ben ;

Shellooe, Rafe ;

Marimuthu, Adhirai ;

Nguyen, Hoa ;

Zhang, Kam Y. J. ;

Artis, Dean R. ;

Schlessinger, Joseph ;

Su, Fei ;

Higgins, Brian ;

Iyer, Raman ;

D'Andrea, Kurt ;

Koehler, Astrid ;

Stumm, Michael ;

Lin, Paul S. ;

Lee, Richard J. ;

Grippo, Joseph ;

Puzanov, Igor ;

Kim, Kevin B. ;

Ribas, Antoni ;

McArthur, Grant A. ;

Sosman, Jeffrey A. ;

Chapman, Paul B. ;

Flaherty, Keith T. ;

Xu, Xiaowei ;

Nathanson, Katherine L. ;

Nolop, Keith .

NATURE, 2010, 467 (7315) :596-599

[5] Ral GTPases: corrupting the exocyst in cancer cells [J].

Camonis, JH ;

White, MA .

TRENDS IN CELL BIOLOGY, 2005, 15 (06) :327-332

[6] A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal [J].

Catalanotti, Federica ;

Reyes, Gloria ;

Jesenberger, Veronika ;

Galabova-Kovacs, Gergana ;

Simoes, Ricardo de Matos ;

Carugo, Oliviero ;

Baccarini, Manuela .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2009, 16 (03) :294-303

[7] Forebrain-specific knockout of B-raf kinase leads to deficits in hippocampal long-term potentiation, learning, and memory [J].

Chen, AP ;

Ohno, M ;

Giese, KP ;

Kühn, R ;

Chen, RL ;

Silva, AJ .

JOURNAL OF NEUROSCIENCE RESEARCH, 2006, 83 (01) :28-38

[8] Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis [J].

Cully, M ;

You, H ;

Levine, AJ ;

Mak, TW .

NATURE REVIEWS CANCER, 2006, 6 (03) :184-192

[9] Association of KRAS p.G13D Mutation With Outcome in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer Treated With Cetuximab [J].

De Roock, Wendy ;

Jonker, Derek J. ;

Di Nicolantonio, Federica ;

Sartore-Bianchi, Andrea ;

Tu, Dongsheng ;

Siena, Salvatore ;

Lamba, Simona ;

Arena, Sabrina ;

Frattini, Milo ;

Piessevaux, Hubert ;

Van Cutsem, Eric ;

O'Callaghan, Chris J. ;

Khambata-Ford, Shirin ;

Zalcberg, John R. ;

Simes, John ;

Karapetis, Christos S. ;

Bardelli, Alberto ;

Tejpar, Sabine .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2010, 304 (16) :1812-1820

[10] In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling [J].

Dumaz, Nicolas ;

Hayward, Robert ;

Martin, Jan ;

Ogilvie, Lesley ;

Hedley, Douglas ;

Curtin, John A. ;

Bastian, Boris C. ;

Springer, Caroline ;

Marais, Richard .

CANCER RESEARCH, 2006, 66 (19) :9483-9491

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