Differential KEAP1/NRF2 mediated signaling widens the therapeutic window of redox-targeting drugs in SCLC therapy.
Samarin Jana, Nůsková Hana, Fabrowski Piotr, Malz Mona, Amtmann Eberhard, Taeubert Minerva J, Pastor-Flores Daniel, Kazdal Daniel, Kurilov Roman, de Vries Nicole, Pink Hannelore, Deis Franziska, Hummel-Eisenbeiss Johanna, Renz Lisa, Kaushal Kamini, Morgen Michael, Dick Tobias P, Hamilton Gerhard, Muckenthaler Martina, Mall Moritz, Lim Bryce, Kanamaru Taishi, Klinke Glynis, Sos Martin L, Frede Julia, Miller Aubry K, Alborzinia Hamed, Gunkel Nikolas
Abstract
Small cell lung cancer (SCLC) patients frequently experience a remarkable response to first-line therapy. Follow up maintenance treatments aim to control residual tumor cells, but generally fail due to cross-resistance, inefficient targeting of tumor vulnerabilities, or dose-limiting toxicity, resulting in relapse and disease progression. Here we show that SCLC cells, similar to their cells of origin, pulmonary neuroendocrine cells, exhibit low activity in pathways protecting against reactive oxygen species (ROS). When exposed to a thioredoxin reductase 1 (TXNRD1) inhibitor, these cells quickly exhaust their ROS-scavenging capacity, regardless of their molecular subtype or resistance to first-line therapy. Importantly, unlike non-cancerous cells, SCLC cells cannot adapt to drug-induced ROS stress due to the suppression of ROS defense mechanisms by multiple layers of gene regulation. By exploiting this difference in oxidative stress management, we safely increase the therapeutic dose of TXNRD1 inhibitors in vivo by pharmacological activation of the NRF2 stress response pathway. This results in improved tumor control without added toxicity to healthy tissues. These findings underscore the therapeutic potential of TXNRD1 inhibitors for maintenance therapy in SCLC.
Key Findings
- SCLC cells and their cells of origin exhibit low activity in ROS-protective pathways.
- TXNRD1 inhibitors exhaust ROS-scavenging capacity in SCLC cells regardless of subtype or therapy resistance.
- Pharmacological activation of NRF2 allows higher therapeutic doses of TXNRD1 inhibitors without added toxicity.
- SCLC cells cannot adapt to drug-induced ROS stress due to suppressed ROS defense mechanisms.
Clinical Significance
The study identifies a novel therapeutic strategy using TXNRD1 inhibitors combined with NRF2 activation to improve tumor control in SCLC patients while minimizing toxicity, offering potential for more effective maintenance therapy.
Citation
Samarin Jana, Nůsková Hana, Fabrowski Piotret al.. Differential KEAP1/NRF2 mediated signaling widens the therapeutic window of redox-targeting drugs in SCLC therapy. Nature communications. 2026-Apr-12.