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The potential of PARP inhibitors in targeted cancer therapy and immunotherapy

Jaromir Hunia1, Karol Gawalski2,3, Aleksandra Szredzka1

  • 1Department of Immunology, Medical University of Warsaw, Warsaw, Poland.

Frontiers in Molecular Biosciences
|December 19, 2022
PubMed

Insights

Poly (ADP-ribose) polymerase inhibitors (PARPi) target DNA damage response pathways in cancer. PARPi combined with immune checkpoint inhibitors (ICIs) show promise for enhanced cancer therapy by boosting anti-tumor immunity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • DNA damage response (DDR) deficiencies drive cancer genome instability.
  • Poly (ADP-ribose) polymerase (PARP) enzymes are crucial in DDR and cell fate determination.
  • PARP inhibitors (PARPi) targeting PARP1/2 are approved cancer therapeutics, particularly for homologous recombination deficiencies (HRD).

Purpose of the Study:

  • To review the roles of PARP1/2 in cellular processes and the mechanisms of PARPi.
  • To explore the synergistic potential of combining PARPi with immune checkpoint inhibitors (ICIs).
  • To discuss diagnostic tools and future perspectives for PARPi-ICI combination therapies.

Main Methods:

  • Literature review of PARP biology, PARPi mechanisms, and clinical trial data.
  • Analysis of preclinical and clinical evidence for PARPi-ICI synergy.
  • Discussion of diagnostic strategies for patient selection.

Main Results:

  • PARPi exploit DDR deficiencies, proving lethal to cancer cells with HRD (e.g., BRCA1/2 defects).
  • PARPi modulate the tumor microenvironment, enhancing immune cell activation and PD-L1 expression.
  • Early clinical data suggest synergistic effects between PARPi and ICIs, indicating improved therapeutic outcomes.

Conclusions:

  • PARPi represent a targeted therapy approach exploiting cancer-specific vulnerabilities.
  • The combination of PARPi and ICIs offers a promising strategy to enhance anti-tumor immunity and patient response.
  • Further research and diagnostic development are essential to optimize PARPi-ICI combination therapies.
Keywords:
BRCADNA repairPARP inhibitorscancerimmune checkpoint inhibitorsimmunotherapysynthetic lethality

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