Replacement of normal with mutant alleles in the genome of normal human cells unveils mutation-specific drug responses
2008
Di Nicolantonio, Federica | Arena, Sabrina | Gallicchio, Margherita | Zecchin, Davide | Martini, Miriam | Flonta, Simona Emilia | Stella, Giulia Maria | Lamba, Simona | Cancelliere, Carlotta | Russo, Mariangela | Geuna, Massimo | Appendino, Giovanni | Fantozzi, Roberto | Medico, Enzo | Bardelli, Alberto
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.
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