Thioredoxin Reductase 1 inhibition triggers ferroptosis in KRAS-independent lung cancers
Andreani, C.; Bartolacci, C.; Melegari, M.; Sargentoni, N.; Luciani, L.; Marucci, A.; Galeazzi, R.; DeNicola, G. M.; Kilgore, J.; Williams, N. S.; Berto, S.; Gaetani, M.; Pattabhi, P.; Osman, S. S.; Mansour, A. T.; Pucciarelli, S.; Galassi, R.; Scaglioni, P. P.
Show abstract
Lung cancers that harbor wild type KRAS (KRAS-WT) represent a molecularly diverse subset of tumors that often lack targeted therapeutic options. Using synthesized gold(I)-based inhibitors, a multi-omics approach, and functional validation, we identified Thioredoxin reductase 1 (TXNRD1), encoding as a selective vulnerability in KRAS-WT and oncogenic KRAS mutant (KM)-independent lung cancer (LC). Mechanistically, TRXR1 blockade induces ferroptosis through glutathione depletion, lipid reactive oxygen species (ROS) accumulation, and HMOX1-dependent iron overload in KRAS-WT LC both in vitro and in vivo. Furthermore, while KM LC cells are intrinsically resistant to TRXR1 inhibition, KMLC cells that acquire resistance to KRAS inhibitors (KRASi) undergo a redox shift that renders them sensitive to TRXR1 inhibition, uncovering a potential novel therapeutic vulnerability in KRASi-refractory tumors. These findings establish TRXR1 as a targetable redox checkpoint in KRAS-WT and KRASi-resistant lung cancers and support further development of TRXR1 inhibitors.
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