Differential KEAP1/NRF2-mediated signaling widens the therapeutic window of redox-targeting drugs in SCLC therapy [seq]

Small cell lung cancer (SCLC) patients experience rapid disease progression despite frequently achieving a complete response to first-line therapy. Maintenance treatments, aiming at controlling residual tumor cells, generally fail due to cross-resistance, inability to target tumor vulnerabilities, or dose-limiting side effects. Here, we show that SCLC cells, like their cell-of-origin, pulmonary neuroendocrine cells (PNECs), exhibit notably low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a novel thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, independent of their molecular subtype and the resistance status against first-line therapy. Importantly, SCLC cells, in contrast to non-cancerous cells, cannot adapt to drug-induced ROS stress because they repress ROS defense enzymes through multiple layers of epigenetic and transcriptional mechanisms. By exploiting this differential ability to manage oxidative stress, we demonstrate that the therapeutic dose of TXNRD1 inhibitors can be safely increased in vivo through pharmacological activation of the NRF2 stress response pathway using Bardoxolon-Methyl (CDDO-Me), leading to improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors in cancers like SCLC, which are marked by reduced ROS-scavenging capacity and strong suppression of adaptive resistance mechanisms.