Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition

Neoplasia. 2021 Sep;23(9):1002-1015. doi: 10.1016/j.neo.2021.06.010. Epub 2021 Aug 8.

Abstract

Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses.

Keywords: FANCD2; GANT61; GLI1; Olaparib; Ovarian Cancer; and Homologous recombination deficiency.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Fanconi Anemia Complementation Group D2 Protein / genetics
  • Fanconi Anemia Complementation Group D2 Protein / metabolism*
  • Female
  • Hedgehog Proteins / antagonists & inhibitors
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Homologous Recombination / physiology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Mice, Transgenic
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Phthalazines / pharmacology
  • Phthalazines / therapeutic use
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / physiology
  • Xenograft Model Antitumor Assays / methods
  • Zinc Finger Protein GLI1 / antagonists & inhibitors
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • Fancd2 protein, mouse
  • Fanconi Anemia Complementation Group D2 Protein
  • GANT 61
  • Gli1 protein, mouse
  • Hedgehog Proteins
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Pyridines
  • Pyrimidines
  • Zinc Finger Protein GLI1
  • olaparib