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
[41]   Chemosensitivity linked to p73 function [J].
Irwin, MS ;
Kondo, K ;
Marin, MC ;
Cheng, LS ;
Hahn, WC ;
Kaelin, WG .
CANCER CELL, 2003, 3 (04) :403-410
[42]   Heat shock protein 90 as a molecular target for cancer therapeutics [J].
Isaacs, JS ;
Xu, WP ;
Neckers, L .
CANCER CELL, 2003, 3 (03) :213-217
[43]   Oncogene addiction: Sometimes a temporary slavery [J].
Jonkers, J ;
Berns, A .
CANCER CELL, 2004, 6 (06) :535-538
[44]   Choosing anticancer drug targets in the postgenomic era [J].
Kaelin, WG .
JOURNAL OF CLINICAL INVESTIGATION, 1999, 104 (11) :1503-1506
[45]  
KAELIN WG, 2004, SCI STKE, pPE12
[46]   Systematic functional analysis of the Caenorhabditis elegans genome using RNAi [J].
Kamath, RS ;
Fraser, AG ;
Dong, Y ;
Poulin, G ;
Durbin, R ;
Gotta, M ;
Kanapin, A ;
Le Bot, N ;
Moreno, S ;
Sohrmann, M ;
Welchman, DP ;
Zipperlen, P ;
Ahringer, J .
NATURE, 2003, 421 (6920) :231-237
[47]   Consequences of nonadaptive alterations in cancer [J].
Kamb, A .
MOLECULAR BIOLOGY OF THE CELL, 2003, 14 (06) :2201-2205
[48]   Mutation load, functional overlap, and synthetic lethality in the evolution and treatment of cancer [J].
Kamb, A .
JOURNAL OF THEORETICAL BIOLOGY, 2003, 223 (02) :205-213
[49]   Intracellular targets of cyclin-dependent kinase inhibitors: identification by affinity chromatography using immobilised inhibitors [J].
Knockaert, M ;
Gray, N ;
Damiens, E ;
Chang, YT ;
Grellier, P ;
Grant, K ;
Fergusson, D ;
Mottram, J ;
Soete, M ;
Dubremetz, JF ;
Le Roch, K ;
Doerig, C ;
Schultz, PG ;
Meijer, L .
CHEMISTRY & BIOLOGY, 2000, 7 (06) :411-422
[50]   Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of an S phase checkpoint [J].
Krek, W ;
Xu, GF ;
Livingston, DM .
CELL, 1995, 83 (07) :1149-1158