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

Chinnadurai Mani, Kaushlendra Tripathi, Sandeep Chaudhary, Ranganatha R. Somasagara, Rodney P. Rocconi, Chiquito Crasto, Mark Reedy, Mohammad Athar, Komaraiah Palle

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1002-1015
Number of pages14
JournalNeoplasia (United States)
Volume23
Issue number9
DOIs
StatePublished - Sep 2021

Keywords

  • FANCD2
  • GANT61
  • GLI1
  • Homologous recombination deficiency
  • Olaparib
  • Ovarian Cancer

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