Ribonucleotide Reductase Inhibition Triggers Ferroptosis in Genetically Defined Subsets of Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is responsible for the majority of cancer-related mortality worldwide. Lung adenocarcinoma 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 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 oncogene-driven lung adenocarcinoma. Transcriptomic analysis of more than 27,000 real-world samples of patients with NSCLC revealed that RNR subunits (RRM1 and RRM2) are significantly upregulated in TP53-mutated NSCLC and are correlated with significantly poor prognosis in multiple oncogene-driven lung adenocarcinoma. Using pharmacologic and genetic approaches to inhibit RNR in lung adenocarcinoma models, we assessed functional consequences through molecular, biochemical, and imaging techniques. RNR inhibition induced appreciable replication stress and triggered DNA damage, leading to cell death in lung adenocarcinoma 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 lung adenocarcinoma cells can be selectively targeted. Our study establishes RNR inhibition as a potent strategy to selectively induce ferroptosis in oncogene-addicted lung adenocarcinoma, 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 lung adenocarcinoma. SIGNIFICANCE: Our findings highlight RNR as a promising therapeutic target in oncogene-driven lung adenocarcinoma. By demonstrating that RNR inhibition induces ferroptosis, our study opens up new possibilities for developing targeted therapies that selectively eliminate cancer cells in lung adenocarcinoma, paving the way for personalized treatment strategies and potentially overcoming resistance to current therapies.