NQO1 is a determinant for cellular sensitivity to anti-tumor agent Napabucasin

摘要

Napabucasin (NAPA) is thought to be a potent cancer stemness inhibitor in different types of cancer cell lines. While it has shown promising activity in early phase clinical trials, two recent phase III NAPA clinical trials failed to meet the primary endpoint of overall survival. The reason for the failure is not clear, but a possible way to revive the clinical trial is to stratify patients with biomarkers that could predict NAPA response. Here, we report the identification of NAD(P)H dehydrogenase 1 (NQO1) as a major determinant of NAPA efficacy. A proteomic profiling of cancer cell lines revealed that NQO1 abundance is negatively correlated with IC 50 ; in vitro assays showed that NAPA is a substrate for NQO1, which mediates the generation of ROS that leads to cell death. Furthermore, activation of an NQO1 transcription factor NRF2 by chemicals, including an FDA approved drug, can increase the NAPA cytotoxicity. Our findings suggest a potential use of NQO1 expression as a companion diagnostic test to identify patients in future NAPA trials and a combination strategy to expand the application of NAPA-based regimens for cancer therapy.