@article{81e0c0b740054ac6ba333d7ac37b6b96,
title = "Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors",
abstract = "Therapeutic drugs that block DNA repair, including poly(ADP-ribose) polymerase (PARP) inhibitors, fail due to lack of tumor-selectivity. When PARP inhibitors and β-lapachone are combined, synergistic antitumor activity results from sustained NAD(P)H levels that refuel NQO1-dependent futile redox drug recycling. Significant oxygen-consumption-rate/reactive oxygen species cause dramatic DNA lesion increases that are not repaired due to PARP inhibition. In NQO1+ cancers, such as non-small-cell lung, pancreatic, and breast cancers, cell death mechanism switches from PARP1 hyperactivation-mediated programmed necrosis with β-lapachone monotherapy to synergistic tumor-selective, caspase-dependent apoptosis with PARP inhibitors and β-lapachone. Synergistic antitumor efficacy and prolonged survival were noted in human orthotopic pancreatic and non-small-cell lung xenograft models, expanding use and efficacy of PARP inhibitors for human cancer therapy.",
keywords = "ARQ761, NQO1, NQO1 bioctivatable drugs, NSCLC, Olaparib, PARP1, PDA, ROS, Rucaparib, combination chemotherapy, synthetic lethality, β-lapachone",
author = "Xiumei Huang and Motea, {Edward A.} and Moore, {Zachary R.} and Jun Yao and Ying Dong and Gaurab Chakrabarti and Kilgore, {Jessica A.} and Silvers, {Molly A.} and Patidar, {Praveen L.} and Agnieszka Cholka and Farjana Fattah and Yoonjeong Cha and Anderson, {Glenda G.} and Rebecca Kusko and Michael Peyton and Jingsheng Yan and Xie, {Xian Jin} and Venetia Sarode and Williams, {Noelle S.} and Minna, {John D.} and Muhammad Beg and Gerber, {David E.} and Bey, {Erik A.} and Boothman, {David A.}",
note = "Funding Information: Special thanks to Dr. Julia Meade for her review. We are grateful to UTSW SCCC (5P30CA142543) for support of cores (Bioinformatics, Biomarker Research, and Preclinical Pharmacology [PK]). Preclinical Pharmacology Core was supported by institutional funds from the Institute for Innovations in Medical Technology (IIMT) and CPRIT (RP110708-C3) (to N.S.W.). Work in NSCLC and breast cancers were supported by NCI (CA102792) (to D.A.B.) and UTSW-MD Anderson SPORE in lung cancer (P50CA70907) (to J.D.M.). Work in PDA was supported by AACR/PanCan grants 12-60-25-BOOT and 15-65-25-BOOT (to D.A.B.). D.A.B., Y.D., and E.A.B. declare US patent application, ?Methods of treating cancer comprising targeting NQO1? (13/820,127). D.A.B., X.H., and Z.R.M. declare US patent applications, ?Compounds and anti-tumor NQO1 substrates? (14/351, 8961) and ?Tumor-selective combination therapy? (TF13048; international PCT/US2014/033400). D.E.G. receives funding for clinical trials from ArQule, Inc., grants SCCC-10Y11 ARQ-761 and SCCC-15Y11. Publisher Copyright: {\textcopyright} 2016",
year = "2016",
month = dec,
day = "12",
doi = "10.1016/j.ccell.2016.11.006",
language = "English (US)",
volume = "30",
pages = "940--952",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}