Chromatin-Bound PARP1 Correlates with Upregulation of Inflammatory Genes in Response to Long-Term Treatment with Veliparib
Alvarado-Cruz, I.; Mahmoud, M.; Khan, M.; Zhao, S.; Oeck, S.; Meas, R.; Clairmont, K.; Quintana, V.; Zhu, Y.; Porciuncula, A.; Wyatt, H.; Ma, S.; Shyr, Y.; Kong, Y.; LoRusso, P. M.; Laverty, D.; Nagel, Z. D.; Schalper, K. A.; Krauthammer, M.; Sweasy, J. B.
Show abstract
Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat human HCC1937 BRCA1 mutant and isogenic BRCA1-complemented cells for three weeks with veliparib, a PARP inhibitor. We show that long-term treatment with veliparib results in chromatin-bound PARP1 in the BRCA1 mutant cells, and that this correlates with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/ signalling effector stimulator of interferon genes (STING) pathway. In contrast, long-term treatment of isogenic BRCA1-complemented cells with veliparib does not result in chromatin-associated PARP or significant upregulation of the inflammatory response. Our results suggest that long-term veliparib treatment may prime BRCA1 mutant tumors for positive responses to immune checkpoint blockade.
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