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GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway

Hiroshi Ikeuchi1,2, Yusuke Matsuno3, Rika Kusumoto-Matsuo3

  • 1Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.

Oncogene
|August 2, 2024
PubMed

Insights

A new screening platform identified SMO and GLI1 as markers for resistance to DNA damage repair drugs like olaparib. Inhibiting GLI1 shows promise for treating cancers with defective DNA repair mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Identifying anticancer drug mechanisms is crucial for new drug development.
  • A comprehensive screening platform can identify predictive markers for drug efficacy.

Purpose of the Study:

  • To establish and validate a comprehensive oncogene screening platform (MANO panel) for identifying drug efficacy markers.
  • To investigate the role of SMO and GLI1 in resistance to DNA damage repair inhibitors.

Main Methods:

  • Developed a screening platform with 68 oncogenes and 243 genetic variants.
  • Validated the platform using EGFR, BRAF, and MAP2K1 targeted drugs.
  • Screened a BRCA2-knockout DLD1 cell line (DLD1-KO) for drug resistance markers.
  • Performed gene set enrichment analysis and assessed DNA damage repair pathways (HR and NER).
  • Evaluated the efficacy of a GLI1 inhibitor and combination therapy in vitro and in vivo.

Main Results:

  • The MANO panel successfully validated predictive markers for drug efficacy.
  • SMO and GLI1 expression conferred resistance to olaparib in DLD1-KO cells.
  • GLI1 overexpression upregulated homologous recombination (HR) repair genes and enhanced nucleotide excision repair (NER) activity.
  • GLI1 inhibition demonstrated efficacy against GLI1-overexpressing DLD1-KO cells.
  • Combination therapy of olaparib and GLI1 inhibitor showed synergistic effects.

Conclusions:

  • The developed screening platform is a valuable tool for identifying drug sensitivity biomarkers and aiding drug development.
  • GLI1 is implicated in resistance to DNA damage repair inhibitors through modulation of DNA repair pathways.
  • GLI1 inhibition represents a potential therapeutic strategy for cancers with defective DNA damage repair, possibly in combination with PARP inhibitors.

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