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.

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

DI NICOLANTONIO, Federica;ARENA, Sabrina;GALLICCHIO, Margherita;MARTINI, MIriam;LAMBA, SIMONA ELENA;Russo M;FANTOZZI, Roberto;MEDICO, Enzo;BARDELLI, Alberto
2008

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.
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Cancer mutation; Oncogene addiction; Targeted therapies; Tumor progression model; KRAS; BRAF; EGFR; Pharmacogenomics
Di Nicolantonio F ; Arena S; Gallicchio M; Zecchin D; Martini M; Flonta SE; Stella GM; Lamba S; Cancelliere C; Russo M; Geuna M; Appendino G; Fantozzi R; Medico E; Bardelli A
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/133644
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