FIGURE 4.

Proposed mechanism of IR and β-lap radiosensitization. NSCLC tumors contain high levels of NQO1 compared to normal tissues. In the presence of NQO1, β-lap causes ROS-induced oxidative base DNA damage, which eventually leads to the formation of SSBs that activate PARP1. IR induces massive SSBs through contact with DNA and oxidized bases due to water radiolysis that require PARP1 and BER to resolve. This combination therapy pushes cumulative amount of DNA damage high enough that overwhelms and hyperactivates PARP1 during DNA damage response and repair, leading to programmed necrosis. Thus, NQO1 may be used as a predictive biomarker for selective targeting of NQO1-overexpressing cancers with low-dose IR in combination with NQO1-bioactivatable agents as radiosensitizers.