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

[1] USE OF A SCREEN FOR SYNTHETIC LETHAL AND MULTICOPY SUPPRESSEE MUTANTS TO IDENTIFY 2 NEW GENES INVOLVED IN MORPHOGENESIS IN SACCHAROMYCES-CEREVISIAE [J].

BENDER, A ;

PRINGLE, JR .

MOLECULAR AND CELLULAR BIOLOGY, 1991, 11 (03) :1295-1305

[2] shRNA libraries and their use in cancer genetics [J].

Bernards, Rene ;

Brummelkamp, Thijn R. ;

Beijersbergen, Roderick L. .

NATURE METHODS, 2006, 3 (09) :701-706

[3] Oncogenic pathway signatures in human cancers as a guide to targeted therapies [J].

Bild, AH ;

Yao, G ;

Chang, JT ;

Wang, QL ;

Potti, A ;

Chasse, D ;

Joshi, MB ;

Harpole, D ;

Lancaster, JM ;

Berchuck, A ;

Olson, JA ;

Marks, JR ;

Dressman, HK ;

West, M ;

Nevins, JR .

NATURE, 2006, 439 (7074) :353-357

[4] Integrative genomic approaches identify IKBKE as a breast cancer oncogene [J].

Boehm, Jesse S. ;

Zhao, Jean J. ;

Yao, Jun ;

Kim, So Young ;

Firestein, Ron ;

Dunn, Ian F. ;

Sjostrom, Sarah K. ;

Garraway, Levi A. ;

Weremowicz, Stanislawa ;

Richardson, Andrea L. ;

Greulich, Heidi ;

Stewart, Carly J. ;

Mulvey, Laura A. ;

Shen, Rhine R. ;

Ambrogio, Lauren ;

Hirozane-Kishikawa, Tomoko ;

Hill, David E. ;

Vidal, Marc ;

Meyerson, Matthew ;

Grenier, Jennifer K. ;

Hinkle, Greg ;

Root, David E. ;

Roberts, Thomas M. ;

Lander, Eric S. ;

Polyak, Kornelia ;

Hahn, William C. .

CELL, 2007, 129 (06) :1065-1079

[5] RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years [J].

Bowen, DT ;

Frew, ME ;

Hills, R ;

Gale, RE ;

Wheatley, K ;

Groves, MJ ;

Langabeer, SE ;

Kottaridis, PD ;

Moorman, AV ;

Burnett, AK ;

Linch, DC .

BLOOD, 2005, 106 (06) :2113-2119

[6] DLD-1 AND HCT-15 CELL-LINES DERIVED SEPARATELY FROM COLORECTAL CARCINOMAS HAVE TOTALLY DIFFERENT CHROMOSOME CHANGES BUT THE SAME GENETIC-ORIGIN [J].

CHEN, TR ;

DOROTINSKY, CS ;

MCGUIRE, LJ ;

MACY, ML ;

HAY, RJ .

CANCER GENETICS AND CYTOGENETICS, 1995, 81 (02) :103-108

[7] Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic [J].

Cragg, Mark S. ;

Jansen, Elisa S. ;

Cook, Michele ;

Harris, Claire ;

Strasser, Andreas ;

Scott, Clare L. .

JOURNAL OF CLINICAL INVESTIGATION, 2008, 118 (11) :3651-3659

[8] An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth [J].

Crowder, C ;

Kopantzev, E ;

Williams, K ;

Lengel, C ;

Miki, T ;

Rudikoff, S .

ONCOGENE, 2003, 22 (05) :649-659

[9] The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation [J].

DeBerardinis, Ralph J. ;

Lum, Julian J. ;

Hatzivassiliou, Georgia ;

Thompson, Craig B. .

CELL METABOLISM, 2008, 7 (01) :11-20

[10] Analysis of N- and K-ras mutations in the distinctive tumor progression phases of melanoma [J].

Demunter, A ;

Stas, M ;

Degreef, H ;

De Wolf-Peeters, C ;

van den Oord, JJ .

JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2001, 117 (06) :1483-1489

← 1 2 3 4 5 6 7 →