The concept of synthetic lethality in the context of anticancer therapy

被引:1077
作者
Kaelin, WG [1 ]
机构
[1] Howard Hughes Med Inst, Boston, MA 02115 USA
关键词
D O I
10.1038/nrc1691
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Two genes are synthetic lethal if mutation of either alone is compatible with viability but mutation of both leads to death. So, targeting a gene that is synthetic lethal to a cancer-relevant mutation should kill only cancer cells and spare normal cells. Synthetic lethality therefore provides a conceptual framework for the development of cancer-specific cytotoxic agents. This paradigm has not been exploited in the past because there were no robust methods for systematically identifying synthetic lethal genes. This is changing as a result of the increased availability of chemical and genetic tools for perturbing gene function in somatic cells.
引用
收藏
页码:689 / 698
页数:10
相关论文
共 110 条
[1]  
Adams PD, 1996, CURR TOP MICROBIOL, V208, P79
[2]   DEFICIENCY OF RETINOBLASTOMA PROTEIN LEADS TO INAPPROPRIATE S-PHASE ENTRY, ACTIVATION OF E2F-RESPONSIVE GENES, AND APOPTOSIS [J].
ALMASAN, A ;
YIN, YX ;
KELLY, RE ;
LEE, EYHP ;
BRADLEY, A ;
LI, WW ;
BERTINO, JR ;
WAHL, GM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (12) :5436-5440
[3]   Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes [J].
Ashrafi, K ;
Chang, FY ;
Watts, JL ;
Fraser, AG ;
Kamath, RS ;
Ahringer, J ;
Ruvkun, G .
NATURE, 2003, 421 (6920) :268-272
[4]   Identification of modulators of TRAIL-induced apoptosis via RNAi-based phenotypic screening [J].
Aza-Blanc, P ;
Cooper, CL ;
Wagner, K ;
Batalov, S ;
Deveraux, QL ;
Cooke, MP .
MOLECULAR CELL, 2003, 12 (03) :627-637
[5]   Yeast genome-wide drug-induced haploinsufficiency screen to determine drug mode of action [J].
Baetz, K ;
McHardy, L ;
Gable, K ;
Tarling, T ;
Rebérioux, D ;
Bryan, J ;
Andersen, RJ ;
Dunn, T ;
Hieter, P ;
Roberge, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (13) :4525-4530
[6]   Microarrays of small molecules embedded in biodegradable polymers for use in mammalian cell-based screens [J].
Bailey, SN ;
Sabatini, DM ;
Stockwell, BR .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (46) :16144-16149
[7]  
Banerjee D, 1998, CANCER RES, V58, P4292
[8]   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
[9]   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
[10]   Cdk2 knockout mice are viable [J].
Berthet, C ;
Aleem, E ;
Coppola, V ;
Tessarollo, L ;
Kaldis, P .
CURRENT BIOLOGY, 2003, 13 (20) :1775-1785