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Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for

Lingwen Xu1,2, Xiangyu Kong1,2, Bin Zhang1,2

  • 1Institute of Chemical Drugs, Shandong Academy of Pharmaceutical Sciences, Jinan 250101, China.

Pharmaceutics
|March 28, 2026
PubMed

Insights

PARP inhibitors (PARPi) are vital for cancer therapy but face resistance. Combination strategies targeting DNA damage response (DDR) pathways are key to overcoming resistance and improving durable cancer control.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Therapeutic resistance is a major challenge in cancer treatment.
  • The DNA damage response (DDR) network plays a critical role in cancer progression and therapeutic resistance.
  • Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective against tumors with homologous recombination deficiency (HRD), but resistance is common.

Purpose of the Study:

  • To review the mechanisms of PARPi action and resistance.
  • To explore emerging combination strategies for overcoming PARPi resistance.
  • To highlight the importance of understanding DDR regulation for advancing precision cancer therapy.

Main Methods:

  • Review of molecular mechanisms of PARPi action.
  • Analysis of established and emerging PARPi resistance pathways.
  • Summary of preclinical and clinical data on combination therapies involving PARPi.

Main Results:

  • PARPi resistance mechanisms include HR restoration, replication fork protection, RAD51-mediated strand invasion, and metabolic reprogramming.
  • Combination therapies (e.g., with HDAC inhibitors, CDK inhibitors, immune checkpoint blockade, radiation) enhance PARPi efficacy.
  • These combinations target DNA repair pathways and the tumor immune microenvironment.

Conclusions:

  • Overcoming PARPi resistance requires a comprehensive understanding of DDR network regulation.
  • Rationally designed combination regimens are essential for improving adaptive, precision-based cancer therapy.
  • Further research into coordinated DDR regulation will facilitate the development of more effective cancer treatments.
Keywords:
DNA damage responsePARP inhibitorscombination therapyhomologous recombination deficiencyresistancesynthetic lethality

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