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Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells

Isabel Alvarado-Cruz1, Mariam Mahmoud2, Mohammed Khan3

  • 1Department of Cellular and Molecular Medicine, University of Arizona Cancer Center College, Tucson, AZ, USA.

Biochemical Pharmacology
|December 7, 2020
PubMed

Insights

Long-term treatment with poly-ADP-ribose polymerase inhibitors (PARPi) triggers inflammation in BRCA1-deficient cells and increases mutations in normal cells. This suggests PARPi may enhance responses to immune checkpoint blockade therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) are effective against tumors with homology-directed repair defects via synthetic lethality.
  • PARPi mechanisms include catalytic inhibition and chromatin localization.
  • The impact of long-term PARPi treatment on cellular mutation levels and inflammatory responses requires further investigation.

Purpose of the Study:

  • To investigate the effects of long-term veliparib (a PARPi) treatment on BRCA1-mutant and wild-type cells.
  • To determine if veliparib induces increased mutations or an inflammatory response.
  • To explore the correlation between PARP1 levels, inflammatory gene expression, and the cGAS/STING pathway.

Main Methods:

  • Treatment of BRCA1-mutant (HCC1937) and control cells with veliparib for three weeks.
  • Analysis of mutation levels.
  • Assessment of inflammatory gene expression and cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway activation.
  • Quantification of chromatin-bound PARP1 levels.

Main Results:

  • Long-term veliparib treatment induced an inflammatory response in BRCA1-mutant HCC1937 cells.
  • Chromatin-bound PARP1 levels correlated with upregulated inflammatory genes and activated cGAS/STING pathway in BRCA1-mutant cells.
  • Increased mutational load was observed in BRCA1-complemented (wild-type) cells treated with veliparib.

Conclusions:

  • Long-term PARPi treatment can induce distinct responses in BRCA1-mutant and wild-type cells.
  • PARPi may prime both mutant and wild-type tumors for enhanced responses to immune checkpoint blockade.
  • The underlying mechanisms for priming tumors differ between BRCA1-mutant and wild-type contexts.
Keywords:
BRCA1 mutantCancerInflammationPARP chromatin-bound

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