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PARP1-SNAI2 transcription axis drives resistance to PARP inhibitor, Talazoparib

Xia Ding1, Zhou Zhu2,3, John Lapek2,4

  • 1Oncology Research Unit, Pfizer, Inc., San Diego, CA, 92121, USA. xia.ding2@pfizer.com.

Scientific Reports
|July 21, 2022
PubMed

Insights

Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective against BRCA-mutated cancers, but resistance emerges in non-BRCA mutated tumors. This study links epithelial-mesenchymal transition (EMT) to PARPi resistance, identifying a key pathway for potential therapeutic targeting.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) show efficacy in BRCA-mutated cancers due to synthetic lethality.
  • PARPi also benefit non-BRCA mutated tumors, likely via PARP1-DNA trapping, but resistance remains a challenge.
  • Mechanisms of PARPi resistance in non-BRCA mutated tumors are less understood than in BRCA-mutated settings.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to the PARP inhibitor Talazoparib in non-BRCA mutated tumor cells.
  • To identify potential therapeutic targets to overcome Talazoparib resistance in these tumors.

Main Methods:

  • Correlation analysis between epithelial-mesenchymal transition (EMT) signatures and Talazoparib resistance.
  • Genetic profiling and molecular analyses to identify key genes and pathways involved in resistance.
  • Investigating the role of PARP1, SNAI2, and CHD1L in Talazoparib resistance through gene manipulation and promoter binding assays.

Main Results:

  • A strong correlation was observed between EMT signature and Talazoparib resistance in non-BRCA mutated tumor cells.
  • Talazoparib treatment or PARP1 depletion induced SNAI2, a key EMT transcription factor, contributing to resistance.
  • PARP1 was found to directly bind and suppress SNAI2 transcription; its depletion or Talazoparib treatment released this suppression.
  • Depletion of the chromatin remodeler CHD1L reduced SNAI2 expression and reversed acquired Talazoparib resistance.

Conclusions:

  • The PARP1/CHD1L/SNAI2 transcriptional axis is a critical driver of Talazoparib resistance in non-BRCA mutated tumors.
  • Targeting this axis offers a potential strategy to re-sensitize these tumors to Talazoparib therapy.

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