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

Domenii publicaţii > Ştiinţe medicale + Tipuri publicaţii > Articol în revistã ştiinţificã

Autori: Federica Di Nicolantonio, Sabrina Arena, Margherita Gallicchio, Davide Zecchin, Miriam Martini, Simona Emilia Flonta, Giulia Maria Stella, Simona Lamba, Carlotta Cancelliere, Mariangela Russo, Massimo Geuna, Giovanni Appendino, Roberto Fantozzi, Enzo Medi

Editorial: prof. Bert Vogelstein, PNAS, vol. 105 no. 52 , p.20864-2086, 2008.


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.

Cuvinte cheie: cancer mutation, oncogene addiction, pharmacogenomic, targeted therapies, tumor progression model