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Mechanisms of PARP Inhibitor Resistance: From Replication Gap Biology and Transcription-Replication Conflicts to

Abinawanto1, Alfi Sophian2

  • 1Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Indonesia, Depok, Indonesia.

Environmental and Molecular Mutagenesis
|August 13, 2026
PubMed

Insights

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) offer precision oncology for HR-deficient cancers. Resistance mechanisms are being uncovered, guiding new therapeutic strategies and biomarker development for improved patient outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective against homologous recombination (HR)-deficient cancers, particularly those with BRCA1/2 mutations.
  • Emergence of resistance to PARPi limits long-term clinical benefit in precision oncology.
  • Understanding PARPi response and resistance mechanisms is crucial for advancing cancer therapy.

Purpose of the Study:

  • To review and synthesize emerging mechanistic insights into PARP inhibitor (PARPi) response and resistance.
  • To re-evaluate established resistance mechanisms within an updated framework.
  • To propose novel therapeutic strategies and an integrated biomarker approach for PARPi-resistant cancers.

Main Methods:

  • Literature review synthesizing recent mechanistic insights into PARPi response and resistance.
  • Analysis of emerging evidence reframing PARPi cytotoxicity through a transcription-replication conflict model.
  • Discussion of novel therapeutic strategies including PROTAC-based PARP1 degraders and combination therapies.

Main Results:

  • PARPi cytotoxicity in HR-deficient cells is linked to single-stranded DNA gaps, not double-strand breaks, via a transcription-replication conflict model.
  • Resistance mechanisms involve restoring replication gap suppression or resolving transcription-replication stress.
  • DNA ligase III identified as a vulnerability in 53BP1-deficient resistant tumors; PROTACs offer a strategy to overcome resistance.
  • Combination strategies with ATR inhibitors show promise in PARPi-resistant HR-deficient ovarian cancer.

Conclusions:

  • An updated framework for understanding PARPi response and resistance is proposed, emphasizing transcription-replication conflicts and single-stranded DNA gaps.
  • Novel therapeutic strategies, including PROTACs and ATR inhibitor combinations, show potential for overcoming resistance.
  • An integrated biomarker framework is suggested for dynamic tracking of resistance, combining HRD assays, RAD51 analysis, replication gap profiling, and ctDNA monitoring.
Keywords:
ATR inhibitorsBRCA1/2 resistance mechanismsPARP inhibitorsPROTAC degradershomologous recombination deficiencyssDNA replication gapstranscription–replication conflicts

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