Integrated genomic and pharmacological approaches to identify synthetic lethal genes as cancer therapeutic targets.
Various types of cancers are generated through mutations or dysregulations of oncogenes/tumor suppressor genes involved in cell cycles and signaling transduction pathways. To identify cancer therapeutic targets whose inhibition selectively kills cancer cells, synthetic lethal screening is being developed to identify genes whose intervention suppresses tumor progression only when combined with the dysregulation of the genes. The recent emergence of genomic technologies, including microarray, RNA interference and chemogenomics, provides platforms to realize this concept. This review introduces the research that could successfully identify synthetic lethal genes in cancer cells harboring major gene alterations such as p53, RB, K-Ras, or Myc. We also illustrate remarkable candidate targets that were identified by synthetic lethal screening to find chemosensitizers for paclitaxel and cisplatin. Next, we introduce the chemogenomics approaches that explore chemical compounds that exhibit synthetic lethality to cancer gene alterations. Although the synthetic lethal compounds are of great interest in terms of cancer drug development, a method of identifying target proteins for the phenotypic compounds has been elusive. Finally, we demonstrate several noteworthy techniques to identify target proteins for the compounds: a Connectivity Map that compares expression profiles of compound-treated cells by pattern-matching algorithms; an siRNA/compound co-treatment assay to find enhancer genes for the phenotypes of compounds; and a state-of-the-art proteomics approach that modifies classical compound-immobilized affinity chromatography. The integration of genomic and pharmacological analyses would significantly accelerate the identification of cancer-specific synthetic lethal targets.
Mizuarai
Shinji
S
Department of Cancer Research, Banyu Tsukuba Research Institute, Merck Research Laboratory, Tsukuba, Ibaraki 300-2611, Japan.
Irie
Hiroki
H
Schmatz
Dennis M
DM
Kotani
Hidehito
H
D020869:Gene Expression Profiling; D020868:Gene Silencing; D018390:Gene Targeting; D005804:Genes, Lethal; D005813:Genes, Synthetic; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D040901:Proteomics