Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA.
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.
Ferrer
Miriam
M
Department of Medical Oncology, Division of Gene Therapy, VU University Medical Center, Amsterdam, The Netherlands.
de Winter
Johan P
JP
Mastenbroek
D C Jeroen
DC
Curiel
David T
DT
Gerritsen
Winald R
WR
Giaccone
Giuseppe
G
Kruyt
Frank A E
FA
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002457:Cell Extracts / Q000276:immunology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052241:Fanconi Anemia Complementation Group G Protein; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy*; D009687:Nuclear Proteins / Q000032:analysis / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002457:Cell Extracts; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C499905:FANCD2 protein, human; C499909:FANCG protein, human; C120277:Fanca protein, mouse; C499904:Fancd2 protein, mouse; C499910:Fancg protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D052241:Fanconi Anemia Complementation Group G Protein; D009687:Nuclear Proteins; D002945:Cisplatin