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Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20864-9. doi: 10.1073/pnas.0808757105. Epub 2008 Dec 23.

Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses.

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1
Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, I-10060 Candiolo, Turin, Italy.

Abstract

Mutations in oncogenes and tumor suppressor genes are responsible for tumorigenesis and represent favored therapeutic targets in oncology. We exploited homologous recombination to knock-in individual cancer mutations in the genome of nontransformed human cells. Sequential introduction of multiple mutations was also achieved, demonstrating the potential of this strategy to construct tumor progression models. Knock-in cells displayed allele-specific activation of signaling pathways and mutation-specific phenotypes different from those obtainable by ectopic oncogene expression. Profiling of a library of pharmacological agents on the mutated cells showed striking sensitivity or resistance phenotypes to pathway-targeted drugs, often matching those of tumor cells carrying equivalent cancer mutations. Thus, knock-in of single or multiple cancer alleles provides a pharmacogenomic platform for the rational design of targeted therapies.

PMID:
19106301
PMCID:
PMC2634925
DOI:
10.1073/pnas.0808757105
[Indexed for MEDLINE]
Free PMC Article
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