Abstract Background: Non-small-cell lung cancer (NSCLC) is responsible for the majority of cancer-related mortality worldwide. Lung adenocarcinoma (LUAD) is the most common NSCLC subtype. Despite advances in targeted therapies, treatment resistance remains a critical challenge. Ribonucleotide reductase (RNR), a crucial enzyme in deoxyribonucleotide triphosphate (dNTP) biosynthesis, is frequently upregulated in cancer, contributing to genomic instability and poor prognosis in multiple malignancies. However, the role of the RNR complex in driving tumorigenesis is not fully understood in oncogenic-driven LUAD. Experimental Design: Experimental DesignTranscriptomic analysis of more than 27, 000 real-world NSCLC patient samples revealed that RNR subunits (RRM1 and RRM2) are significantly upregulated in TP53-mutated NSCLC and correlated with significantly poor prognosis in multiple oncogene-driven LUAD. Using pharmacologic and genetic approaches to inhibit RNR in LUAD models, we assessed functional consequences through molecular, biochemical, and imaging techniques. Results: RNR inhibition induced appreciable replication stress and triggered DNA damage, leading to cell death in LUAD cells. Notably, we uncovered that RNR suppression preferentially induced ferroptosis, an iron-dependent cell death driven by lipid peroxidation. This represents a previously unrecognized mechanism of RNR-mediated cell death by which mutant LUAD cells can be selectively targeted. Conclusions: Our study establishes RNR inhibition as a potent strategy to selectively induce ferroptosis in oncogenic addicted LUAD, offering a new therapeutic avenue for genetically defined patient subgroups. Targeting nucleotide metabolism could serve as an effective approach to overcome treatment resistance and improve clinical outcomes for patients with high-risk LUAD. By demonstrating that RNR inhibition induces ferroptosis, a unique form of cell death, our study opens up new possibilities for developing targeted therapies that selectively eliminate cancer cells in LUAD. These insights pave the way for personalized treatment strategies, improving therapeutic efficacy and potentially overcoming resistance to current therapies. Translating RNR-targeted approaches into clinical practice could significantly enhance patient outcomes by addressing the metabolic vulnerabilities of LUAD. Citation Format: Triparna Sen. Ribonucleotide reductase inhibition triggers ferroptosis in genetically defined NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB457.
Triparna Sen (Fri,) studied this question.