Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors

• DOI: 10.1016/j.ccell.2016.11.006
• Publication Date: 2016-12-12T19:51:33Z
• Authors: Xiumei Huang; Edward A. Motea; Zachary R. Moore; Jun Yao; Ying Dong; Gaurab Chakrabarti; Jessica A. Kilgore; Molly A. Silvers; Praveen L. Patidar; Agnieszka Cholka; Farjana Fattah; Yoonjeong Cha; Glenda G. Anderson; Rebecca Kusko; Michael Peyton; Jingsheng Yan; Xian-Jin Xie; Venetia Sarode; Noelle S. Williams; John D. Minna; Muhammad Beg; David E. Gerber; Erik A. Bey; David A. Boothman
• Keywords: PARP1; PARP inhibitor

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.