title: 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.
authors.affiliation: Laboratory of Molecular Genetics, Institute for Cancer Research and Treatment, University of Turin Medical School, I-10060 Candiolo, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Margherita
authors.initials: M
authors.lastname: Gallicchio
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.forename: Simona Emilia
authors.initials: SE
authors.lastname: Flonta
authors.forename: Giulia Maria
authors.initials: GM
authors.lastname: Stella
authors.forename: Simona
authors.initials: S
authors.lastname: Lamba
authors.forename: Carlotta
authors.initials: C
authors.lastname: Cancelliere
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.forename: Massimo
authors.initials: M
authors.lastname: Geuna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055879:Gene Knock-In Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents