Abstract 787: DNA repair and metabolism inhibitors are tumor-selective when combined with NQO1 bioactivatable drugs for therapy against pancreatic and nonsmall cell lung cancers
Authors: Xiumei Huang, Zachary Moore, Xiuquan Luo, Gaurab Chakrabarti, Mariya Ilcheva, Rolf Brekken, Sandeep Burma, Jinming Gao, Ralph Deberardinis, William Bornmann, Paul Hergenrother, David A. Boothman
Journal: Cancer Research (2014)

Abstract The major problem plaguing DNA repair and metabolic inhibitors is their lack of tumor-selectivity, resulting in unwanted toxicities. In contrast, NAD(P)H:quinone oxidoreductase 1 (NQO1) bioactivatable drugs (e.g., ß-lapachone (ß-lap) and deoxynyboquinine (DNQ) and their derivatives) offer exquisite tumor-selectivity, with one form of the drug, ARQ761, currently in Phase I clinical trials against solid cancers, most of which have elevated levels of NQO1; pancreatic and nonsmall cell lung cancers (NSCLC) have the highest levels of this two-electron oxidoreductase. NQO1 levels are elevated during early steps of carcinogenesis in most solid cancers in response to activated K-Ras, c-Myc or other oncogenic drivers, as well as re-expression of human telomerase (hTERT). NQO1 catalyzes an unique futile redox cycle using either of these two unique classes of NQO1 bioactivatable drugs, resulting in super-lethal doses of hydrogen peroxide; in fact one mole of ß-lap used by NQO1 produces &amp;gt;60 moles H2O2 in 2 mins. The elevated levels of H2O2 generates tremendous DNA lesions (e.g., 8-oxoguanine formation) that ultimately results in massive levels of DNA single strand breaks. The H2O2 generated also results in release of ERCa2+ and culminates in the hyperactivation of Poly(ADP-ribose) polymerase (PARP1). GAPDH is then inhibited initially by direct suppression by H2O2 and then by posttranslational modification, resulting in accumulation of glyceraldehyde-3phosphate (GA3P). This unique, NQO1-dependent tumor-selective hyperactivation of PARP1 results in simultaneous losses of NAD+ (generated by the NQO1 futile redox cycle) and ATP, with suppressed recovery by inhibition of glycolysis (by inhibition of GAPDH) and the Krebs cycle through suppression of pyruvate production. Understanding the mechanism of action of these two classes of unique drugs has allowed tumor-selective combination therapies with DNA damaging agents, DNA repair inhibitors, and more recently metabolic inhibitors, such as agents that block NaMPt and GLS1. Addition of these inhibitors, in turn, results in a dramatic lowering of the required doses of NQO1 bioactivatable drugs-a true synergy is established with nontoxic levels of drugs combined to achieve one log or greater loss of colony forming ability. This work is supported by grants from Texas CPRIT, AACR/PanCan Action Network and NIH R01 CA102792-11 to DAB. Citation Format: Xiumei Huang, Zachary Moore, Xiuquan Luo, Gaurab Chakrabarti, Mariya Ilcheva, Rolf Brekken, Sandeep Burma, Jinming Gao, Ralph Deberardinis, William Bornmann, Paul Hergenrother, David A. Boothman. DNA repair and metabolism inhibitors are tumor-selective when combined with NQO1 bioactivatable drugs for therapy against pancreatic and nonsmall cell lung cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 787. doi:10.1158/1538-7445.AM2014-787