Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses
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.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- December 2008
- DOI:
- 10.1073/pnas.0808757105
- Bibcode:
- 2008PNAS..10520864D
- Keywords:
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- cancer mutation;
- oncogene addiction;
- pharmacogenomic;
- targeted therapies;
- tumor progression model;
- Biological Sciences:Medical Sciences