Cultures derived from pancreatic cancer xenografts with long-term gemcitabine treatment produce chemoresistant secondary xenografts: Establishment of isogenic gemcitabine-sensitive and -resistant models

Abstract

In attempts to establish sophisticated models to reproduce the process of acquired drug resistance, we transformed normal human pancreatic ductal epithelial cells by introducing genes for multiple cellular factors. We also created isogenic gemcitabine-sensitive and -resistant models by short- and long-term gemcitabine treatment, respectively. These models demonstrated differences in drug resistance in vivo, but not in vitro. Gemcitabine treatment also induced squamous transdifferentiation in xenografts in mice. The transcription factor p63 was identified as a possible resistance-determining factor but was unlikely to be solely responsible for the resistance to gemcitabine. This system would prove useful to discover novel molecular targets to overcome chemotherapy resistance, by allowing the evaluation of molecules of interest in xenograft models after in vitro genetic ablation.