Synthetic Lethal Interaction between Oncogenic KRAS Dependency and STK33 Suppression in Human Cancer Cells

被引：442

作者：

Scholl, Claudia ^{[1
]}

Froehling, Stefan ^{[1
]}

Dunn, Ian F. ^{[2
,3
,4
,5
,6
,7
]}

Schinzel, Anna C. ^{[3
,4
,5
,6
,7
]}

Barbie, David A. ^{[3
,4
,5
,6
,7
,8
]}

Kim, So Young ^{[3
,4
,5
,6
,7
]}

Silver, Serena J. ^{[6
,7
]}

Tamayo, Pablo ^{[6
,7
]}

Wadlow, Raymond C. ^{[8
,9
,10
]}

Ramaswamy, Sridhar ^{[6
,7
,8
,9
,10
,11
]}

Doehner, Konstanze ^{[12
]}

Bullinger, Lars ^{[12
]}

Sandy, Peter ^{[13
,14
]}

Boehm, Jesse S. ^{[6
,7
]}

Root, David E. ^{[6
,7
]}

Jacks, Tyler ^{[6
,7
,13
,14
,15
]}

Hahn, William C. ^{[1
,3
,4
,5
,6
,7
]}

Gilliland, D. Gary ^{[1
,3
,6
,7
,11
,16
,17
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA

[2] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA

[3] Harvard Univ, Dana Farber Canc Inst, Sch Med, Dept Med Oncol, Boston, MA 02115 USA

[4] Harvard Univ, Dana Farber Canc Inst, Sch Med, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[5] Harvard Univ, Dana Farber Canc Inst, Sch Med, Ctr Canc Syst Biol, Boston, MA 02115 USA

[6] Broad Inst Harvard, Cambridge, MA 02142 USA

[7] MIT, Cambridge, MA 02142 USA

[8] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA

[9] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc Res, Boston, MA 02114 USA

[10] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA

[11] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[12] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany

[13] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[14] MIT, Dept Biol, Cambridge, MA 02139 USA

[15] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

[16] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[17] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA

来源：

CELL | 2009年 / 137卷 / 05期

基金：

美国国家卫生研究院;

关键词：

LENTIVIRAL RNAI LIBRARY; K-RAS ONCOGENE; MULTIPLE-MYELOMA; TUMOR-CELLS; N-RAS; GROWTH; SCREEN; MUTATIONS; SURVIVAL; GENES;

D O I：

10.1016/j.cell.2009.03.017

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：

An alternative to therapeutic targeting of oncogenes is to perform "synthetic lethality'' screens for genes that are essential only in the context of specific cancer-causing mutations. We used high-throughput RNA interference (RNAi) to identify synthetic lethal interactions in cancer cells harboring mutant KRAS, the most commonly mutated human oncogene. We find that cells that are dependent on mutant KRAS exhibit sensitivity to suppression of the serine/threonine kinase STK33 irrespective of tissue origin, whereas STK33 is not required by KRAS-independent cells. STK33 promotes cancer cell viability in a kinase activity-dependent manner by regulating the suppression of mitochondrial apoptosis mediated through S6K1-induced inactivation of the death agonist BAD selectively in mutant KRAS-dependent cells. These observations identify STK33 as a target for treatment of mutant KRAS-driven cancers and demonstrate the potential of RNAi screens for discovering functional dependencies created by oncogenic mutations that may enable therapeutic intervention for cancers with "undruggable'' genetic alterations.

引用

页码：821 / 834

页数：14

共 63 条

[41] Targeted cancer therapy [J].

Sawyers, C .

NATURE, 2004, 432 (7015) :294-297

[42] Characterization of a conserved c-terminal motif (RSPRR) in ribosomal protein S6-kinase-1 required for its mammalian target of rapamycin-dependent regulation [J].

Schalm, SS ;

Tee, AR ;

Blenis, J .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (12) :11101-11106

[43] Cancer proliferation gene discovery through functional Genomics [J].

Schlabach, Michael R. ;

Luo, Ji ;

Solimini, Nicole L. ;

Hu, Guang ;

Xu, Qikai ;

Li, Mamie Z. ;

Zhao, Zhenming ;

Smogorzewska, Agata ;

Sowa, Mathew E. ;

Ang, Xiaolu L. ;

Westbrook, Thomas F. ;

Liang, Anthony C. ;

Chang, Kenneth ;

Hackett, Jennifer A. ;

Harper, J. Wade ;

Hannon, Gregory J. ;

Elledge, Stephen J. .

SCIENCE, 2008, 319 (5863) :620-624

[44] Hyperactive Ras in developmental disorders and cancer [J].

Schubbert, Suzanne ;

Shannon, Kevin ;

Bollag, Gideon .

NATURE REVIEWS CANCER, 2007, 7 (04) :295-308

[45] IRF4 addiction in multiple myeloma [J].

Shaffer, Arthur L. ;

Emre, N. C. Tolga ;

Lamy, Laurence ;

Ngo, Vu N. ;

Wright, George ;

Xiao, Wenming ;

Powell, John ;

Dave, Sandeep ;

Yu, Xin ;

Zhao, Hong ;

Zeng, Yuxin ;

Chen, Bangzheng ;

Epstein, Joshua ;

Staudt, Louis M. .

NATURE, 2008, 454 (7201) :226-231

[46] Ras, PI(3)K and mTOR signalling controls tumour cell growth [J].

Shaw, Reuben J. ;

Cantley, Lewis C. .

NATURE, 2006, 441 (7092) :424-430

[47] ALTERED GROWTH OF HUMAN COLON CANCER CELL-LINES DISRUPTED AT ACTIVATED KI-RAS [J].

SHIRASAWA, S ;

FURUSE, M ;

YOKOYAMA, N ;

SASAZUKI, T .

SCIENCE, 1993, 260 (5104) :85-88

[48] Profiling essential genes in human mammary cells by multiplex RNAi screening [J].

Silva, Jose M. ;

Marran, Krista ;

Parker, Joel S. ;

Silva, Javier ;

Golding, Michael ;

Schlabach, Michael R. ;

Elledge, Stephen J. ;

Hannon, Gregory J. ;

Chang, Kenneth .

SCIENCE, 2008, 319 (5863) :617-620

[49] Establishment of a chemical synthetic lethality screen in cultured human cells [J].

Simons, A ;

Dafni, N ;

Dotan, I ;

Oron, Y ;

Canaani, D .

GENOME RESEARCH, 2001, 11 (02) :266-273

[50] KRASD13 promotes apoptosis of human colorectal tumor cells by ReovirusT3D and oxaliplatin but not by tumor necrosis factor-related apoptosis-inducing ligand [J].

Smakman, Niels ;

van den Wollenberg, Diana J. M. ;

Elias, Sjoerd G. ;

Sasazuki, Takehiko ;

Shirasawa, Senji ;

Hoeben, Rob C. ;

Rinkes, Inne H. M. Borel ;

Kranenblug, Onno .

CANCER RESEARCH, 2006, 66 (10) :5403-5408

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