TY - JOUR
T1 - Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells
AU - Alvarado-Cruz, Isabel
AU - Mahmoud, Mariam
AU - Khan, Mohammed
AU - Zhao, Shilin
AU - Oeck, Sebastian
AU - Meas, Rithy
AU - Clairmont, Kaylyn
AU - Quintana, Victoria
AU - Zhu, Ying
AU - Porciuncula, Angelo
AU - Wyatt, Hailey
AU - Ma, Shuangge
AU - Shyr, Yu
AU - Kong, Yong
AU - LoRusso, Patricia M.
AU - Laverty, Daniel
AU - Nagel, Zachary D.
AU - Schalper, Kurt A.
AU - Krauthammer, Michael
AU - Sweasy, Joann B.
N1 - Funding Information:
This work was funded by NCI R21 CA216595-01 to JBS and PML;1UM1CA186689 to PML; 2P01CA092584-16 to Z.N.; Rising Tide Foundation For Clinical Cancer Research Grant to PML, a P30 NIH/NCI Immunotherapy Biomarker supplement to PML and KAS; Department of Defense Grant W81XWH-16-1-0160 to KAS and Stand up to Cancer Translational Grants SU2C-AACR- DT17-15 and SU2C-AACR-DT22-17. MM was supported in part by a generous gift from Stephen Sherwin, M.D.
Funding Information:
JBS research was supported by AbbVie for unrelated work. KAS has served as a consultant or advisor for Celgene, Moderna Therapeutics, Shattuck Labs, AstraZeneca, Abbvie and Pierre-Fabre. He has received research support from Genoptix/Navigate BP (Novartis), Vasculox, Tesaro, Moderna Therapeutics, Takeda Pharmaceuticals, Surface Oncology, Pierre-Fabre Research Institute, Merck and Bristol-Myers Squibb. PML has served as a consultant, advisor or on the Data Safety Monitoring Board for AstraZeneca, Genentech/Roche, AbbVie, Agenus, Agio, Cybrexa, CytomX, FivePrime, Halozyme, Genmab and SOTIO. MM was supported by a generous donation from Stephen Sherwin MD and by T32CA193200.
Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2021/2
Y1 - 2021/2
N2 - 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 (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP–AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.
AB - 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 (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP–AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.
KW - BRCA1 mutant
KW - Cancer
KW - Inflammation
KW - PARP chromatin-bound
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U2 - 10.1016/j.bcp.2020.114359
DO - 10.1016/j.bcp.2020.114359
M3 - Article
C2 - 33285109
AN - SCOPUS:85098722949
VL - 184
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
M1 - 114359
ER -