Multi-Omics Characterisation of NUDT1–CDK4 Co-Activation in Lung Adenocarcinoma and Its Association With Treatment Resistance
Keywords:
lung adenocarcinoma, NUDT1, CDK4, multi-omics, treatment resistance, survivalAbstract
Background: Resistance to targeted and cytotoxic therapy in lung adenocarcinoma may arise from parallel adaptations in genome protection and cell-cycle control.
Objective: We examined the prevalence, biological context and clinical associations of concurrent NUDT1 and CDK4 activation.
Methods: Transcriptomic and copy-number data from two independent lung-adenocarcinoma datasets were analysed. High expression was defined within each cohort using prespecified quantiles. Differential expression, pathway enrichment and survival models adjusted for age, stage and smoking history were performed.
Results: Co-high NUDT1/CDK4 expression occurred in 17.8% and 15.9% of tumours in the discovery and validation datasets, respectively. The phenotype was enriched for E2F targets, G2/M checkpoint activity, reactive-oxygen-species response and DNA-repair signatures. In adjusted analysis, co-high expression was associated with shorter progression-free survival in both datasets, with hazard ratios of 1.61 and 1.49. Tumours with concurrent activation also showed higher frequencies of broad chromosomal gains but no single defining driver mutation. A four-gene downstream signature derived from shared pathway enrichment separated resistant from non-resistant samples with an AUC of 0.76 in an external treatment-response dataset.
Conclusion: Co-activation of NUDT1 and CDK4 defines a reproducible molecular subset of lung adenocarcinoma characterised by proliferative and redox-adaptive programmes. Although the analysis is hypothesis-generating, the cross-cohort consistency supports experimental evaluation of dual-pathway inhibition and prospective validation of the derived signature.
Publication format: research abstract. No full-text manuscript accompanies this record.
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