Abstract 2503: NQO1's role in maintaining the cancer stem cell phenotype in NSCLC

Abstract

Abstract NAD(P)H:quinone oxidoreductase 1 (NQO1) is a phase II detoxifying enzyme responsible for quinone reduction, where it scavenges quinone induced reactive oxygen species. In recent studies, NQO1 has been investigated as a possible drug target due to its overexpression in a number of solid tumors. To this end, treatment with the quinone-analog drug, β-lapachone (ARQ-761), has progressed to Phase II clinical trials. In an effort to better understand the necessity of NQO1 in the overall lifecycle of cancer, our earlier work demonstrated that NQO1 played a vital role in a number of tumorigenic processes including anoikis resistance, and most interestingly alteration of aldehyde dehydrogenase (ALDH) activity. Given that ALDH is a widely reported cancer stem cell marker, and loss of NQO1 leads to a decrease in ALDH activity, we have begun to investigate the effect of NQO1 expression on the non-small cell lung cancer (NSCLC) stem cell population. Here, we present data that demonstrates NQO1 is vital to tumorsphere formation as demonstrated by decreased spheroid formation following NQO1 knocked down with shRNA. We also show that NQO1 appears to be necessary for cancer stem cell renewal as illustrated by decreased serial tumorsphere formation. In addition to these aforementioned data, in extreme limited dilution assays we demonstrate a reduced cancer stem cell frequency in NQO1 knockdown cells as compared to controls. Interestingly, in NQO1 knockdown populations, those cells that do form spheres show a remarkable re-expression of NQO1 as well as a rescue of ALDH activity, further supporting NQO1's role in tumorsphere formation and stem cell maintenance. Future work on this project will involve use of the CRISPR-Cas9 system to generate NQO1 knockout cell lines, drug resistance studies, cancer stem cell marker validation, and in vivo limited dilution assays to definitively demonstrate NQO1's necessity in maintaining the NSCLC stem cell population. Citation Format: Brian Madajewski, Erik A. Bey. NQO1's role in maintaining the cancer stem cell phenotype in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2503.