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National Academy of Sciences, Proceedings of the National Academy of Sciences, 52(105), p. 20864-20869, 2008

DOI: 10.1073/pnas.0808757105

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

Journal article published in 2008 by Federica Di Nicolantonio, Sabrina Arena, Margherita Gallicchio, Davide Zecchin, Miriam Martini ORCID, Simona Emilia Flonta, Flonta Se, Stella Gm, Giulia Maria Stella, Simona Lamba, Carlotta Cancelliere, Mariangela Russo ORCID, Massimo Geuna, Giovanni Appendino, Roberto Fantozzi ORCID and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.