Revealing targeted therapy for human cancer by gene module maps.
A major goal of cancer research is to match specific therapies to molecular targets in cancer. Genome-scale expression profiling has identified new subtypes of cancer based on consistent patterns of variation in gene expression, leading to improved prognostic predictions. However, how these new genetic subtypes of cancers should be treated is unknown. Here, we show that a gene module map can guide the prospective identification of targeted therapies for genetic subtypes of cancer. By visualizing genome-scale gene expression in cancer as combinations of activated and deactivated functional modules, gene module maps can reveal specific functional pathways associated with each subtype that might be susceptible to targeted therapies. We show that in human breast cancers, activation of a poor-prognosis "wound signature" is strongly associated with induction of both a mitochondria gene module and a proteasome gene module. We found that 3-bromopyruvic acid, which inhibits glycolysis, selectively killed breast cells expressing the mitochondria and wound signatures. In addition, inhibition of proteasome activity by bortezomib, a drug approved for human use in multiple myeloma, abrogated wound signature expression and selectively killed breast cells expressing the wound signature. Thus, gene module maps may enable rapid translation of complex genomic signatures in human disease to targeted therapeutic strategies.
Wong
David J
DJ
Programs in Epithelial Biology, Stanford University, Stanford, California 94305, USA.
Nuyten
Dimitry S A
DS
Regev
Aviv
A
Lin
Meihong
M
Adler
Adam S
AS
Segal
Eran
E
van de Vijver
Marc J
MJ
Chang
Howard Y
HY
D000465:Algorithms; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods*; D001330:Electronic Data Processing; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000502:physiology*; D018390:Gene Targeting; D050259:Genes, Mitochondrial; D015316:Genetic Therapy; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D011719:Pyrazines / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014947:Wounds and Injuries / Q000235:genetics
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex