Mutant IDH1-driven cellular transformation increases RAD51-mediated homologous recombination and temozolomide resistance

Cancer Res. 2014 Sep 1;74(17):4836-44. doi: 10.1158/0008-5472.CAN-14-0924. Epub 2014 Jul 17.

Abstract

Isocitrate dehydrogenase 1 (IDH1) mutations occur in most lower grade glioma and not only drive gliomagenesis but are also associated with longer patient survival and improved response to temozolomide. To investigate the possible causative relationship between these events, we introduced wild-type (WT) or mutant IDH1 into immortalized, untransformed human astrocytes, then monitored transformation status and temozolomide response. Temozolomide-sensitive parental cells exhibited DNA damage (γ-H2AX foci) and a prolonged G2 cell-cycle arrest beginning three days after temozolomide (100 μmol/L, 3 hours) exposure and persisting for more than four days. The same cells transformed by expression of mutant IDH1 exhibited a comparable degree of DNA damage and cell-cycle arrest, but both events resolved significantly faster in association with increased, rather than decreased, clonogenic survival. The increases in DNA damage processing, cell-cycle progression, and clonogenicity were unique to cells transformed by mutant IDH1, and were not noted in cells transformed by WT IDH1 or an oncogenic form (V12H) of Ras. Similarly, these effects were not noted following introduction of mutant IDH1 into Ras-transformed cells or established glioma cells. They were, however, associated with increased homologous recombination (HR) and could be reversed by the genetic or pharmacologic suppression of the HR DNA repair protein RAD51. These results show that mutant IDH1 drives a unique set of transformative events that indirectly enhance HR and facilitate repair of temozolomide-induced DNA damage and temozolomide resistance. The results also suggest that inhibitors of HR may be a viable means to enhance temozolomide response in IDH1-mutant glioma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics*
  • DNA Damage / drug effects
  • DNA Damage / genetics
  • DNA Repair / drug effects
  • DNA Repair / genetics
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • G2 Phase Cell Cycle Checkpoints / genetics
  • Glioma / drug therapy
  • Glioma / genetics
  • Homologous Recombination / genetics*
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Mutation / genetics*
  • Rad51 Recombinase / genetics*
  • Temozolomide

Substances

  • Dacarbazine
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Rad51 Recombinase
  • Temozolomide