Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA

Miriam Ferrer, Johan P. De Winter, D. C Jeroen Mastenbroek, David T. Curiel, Winald R. Gerritsen, Giuseppe Giaccone, Frank A E Kruyt

Research output: Contribution to journalArticle

Abstract

Fanconi anemia (FA) is a rare genetic disorder characterized by bone-marrow failure and cellular hypersensitivity to crosslinking agents, including cisplatin. Here, we studied the use of the FA pathway as a possible target for cancer gene therapy with the aim to sensitize tumor cells for cisplatin by interfering with the FA pathway. As proof-of-principle, FA and non-FA lymphoblast-derived tumors were grown subcutaneously in scid mice and treated with two different concentrations of cisplatin. As predicted, the antitumor response was considerably improved in FA tumors. An adenoviral vector encoding a dominant-negative form of FANCA, FANCA600DN, was generated that interfered with endogenous FANCA-FANCG interaction resulting in the disruption of the FA pathway as illustrated by disturbed FANCD2 monoubiquitination. A panel of cell lines, including non-small-cell lung cancer cells, could be sensitized approximately two- to three-fold for cisplatin after Ad.CMV.FANCA600DN infection that may increase upon enhanced infection efficiency. In conclusion, targeting the FA pathway may provide a novel strategy for the sensitization of solid tumors for cisplatin and, in addition, provides a tool for examining the role of the FA pathway in determining chemoresistance in different tumor types.

Original languageEnglish (US)
Pages (from-to)539-546
Number of pages8
JournalCancer Gene Therapy
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2004
Externally publishedYes

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Keywords

  • Adenovirus
  • Chemotherapy
  • Fanconi anemia
  • NSCLC
  • Resistance

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Ferrer, M., De Winter, J. P., Mastenbroek, D. C. J., Curiel, D. T., Gerritsen, W. R., Giaccone, G., & Kruyt, F. A. E. (2004). Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA. Cancer Gene Therapy, 11(8), 539-546. https://doi.org/10.1038/sj.cgt.7700734