TY - JOUR
T1 - Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone
AU - Chakrabarti, Gaurab
AU - Silvers, Molly A.
AU - Ilcheva, Mariya
AU - Liu, Yuliang
AU - Moore, Zachary R.
AU - Luo, Xiuquan
AU - Gao, Jinming
AU - Anderson, Glenda
AU - Liu, Lili
AU - Sarode, Venetia
AU - Gerber, David E.
AU - Burma, Sandeep
AU - DeBerardinis, Ralph J.
AU - Gerson, Stanton L.
AU - Boothman, David A.
N1 - Funding Information:
We are grateful to the UT Southwestern Simmons Comprehensive Cancer Center, NIH/NCI CCSG grant 5P30CA142543 for support of the various cores (Bioinformatics, Biomarker Research, and PK Cores) used in this study. All work in PDA was supported by AACR/PanCan Grants: 14-65-25-BOOT, an AACR/PanCan Action Network George and June Block Family Foundation Innovator Award and grant 15-65-25-BOOT AACR/PanCan Translational Award to DAB. Support for this work was provided by NIH R01 CA102792 and CPRIT Translational grants to J.G. and D.A.B. This work is dedicated to Mrs. Rousemarie Bouley and Mrs. Barbara Schnars.
Publisher Copyright:
© 2015, Nature Publishing Group. All rights reserved.
PY - 2015/11/25
Y1 - 2015/11/25
N2 - Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, β-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. β-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of β-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from β-lap-induced lethality and blunted PARP1 hyperactivation. Combining β-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + β-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.
AB - Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, β-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. β-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of β-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from β-lap-induced lethality and blunted PARP1 hyperactivation. Combining β-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + β-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.
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U2 - 10.1038/srep17066
DO - 10.1038/srep17066
M3 - Article
C2 - 26602448
AN - SCOPUS:84948171903
SN - 2045-2322
VL - 5
JO - Scientific Reports
JF - Scientific Reports
M1 - 17066
ER -