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

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 Medico, Alberto Bardelli

Research output: Contribution to journalArticle

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)20864-20869
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number52
DOIs
Publication statusPublished - Dec 30 2008

Fingerprint

Human Genome
Alleles
Mutation
Pharmaceutical Preparations
Neoplasms
Oncogenes
Phenotype
Pharmacogenetics
Homologous Recombination
Tumor Suppressor Genes
Libraries
Carcinogenesis
Pharmacology
Therapeutics

Keywords

  • Cancer mutation
  • Oncogene addiction
  • Pharmacogenomic
  • Targeted therapies
  • Tumor progression model

ASJC Scopus subject areas

  • General

Cite this

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; 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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 52, 30.12.2008, p. 20864-20869.

Research output: Contribution to journalArticle

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AU - Martini, Miriam

AU - Flonta, Simona Emilia

AU - Stella, Giulia Maria

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