ATR expression as a prognostic biomarker in KRAS-mutated non-small cell lung cancer

The KRAS gene is a member of the Ras protein family. KRAS mutations are prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), even in the Chinese populations, where they account for 10-15% of cases, and are correlated with aggressive disease and poor clinical outcomes. Despite recent breakthroughs in direct KRAS G12C inhibitors (e.g., sotorasib and adagrasib), the therapeutic efficacy of these inhibitors remains limited; the median progression-free survival of KRAS-mutated NSCLC patients rarely exceeds 6 months, and actionable therapies for non-G12C variants are lacking. Based on this foundation, the study aimed to identify novel potential targeted therapeutic strategies for patients with KRAS-mutant NSCLC through systematic target screening.

The following three-step process and selection criteria were employed to identify the KRAS function-related genes: (I) the genes were differentially expressed in the NSCLC tissues compared to the normal tissues; (II) the differentially expressed genes were highly expressed in the KRAS-mutated tissues compared to the KRAS-wild-type NSCLC tissues in The Cancer Genome Atlas (TCGA) cohort; and (III) the genes had a dependency score of >0.9 in the KRAS-mutated NSCLC cell lines from the Cancer Cell Line Encyclopedia based on the dataset. We then examined the prognostic value of the KRAS function-related genes in TCGA cohort (504 lung adenocarcinoma samples) and validated their prognostic value in the GSE72094 dataset (398 lung adenocarcinoma samples). Additionally, we conducted a gene set enrichment analysis (GSEA) to investigate the potential mechanisms by which the candidate genes affected prognosis, and performed a drug sensitivity analysis to identify compounds exhibiting sensitivity to candidate gene expression levels in the KRAS-mutated NSCLC cell lines.

We identified four KRAS function-related genes and showed that ATR expression was significantly associated with overall survival (P=0.008). After adjusting for age, gender and TNM stage (Tumor-Node-Metastasis stage), high ATR expression remained an independent predictor of a worse prognosis in KRAS-mutated NSCLC [hazard ratio (HR) =2.192; P=0.01] in the TCGA cohort, and this prognostic significance was validated in the GSE72094 dataset (HR =2.06; P=0.02). The GSEA results showed that the enriched genes in the ATR high-expression group were significantly associated with ubiquitin mediated proteolysis, pathways in cancer, and the mitogen-activated protein kinase signaling pathway compared to the ATR low-expression group. Additionally, the drug sensitivity analysis identified two compounds (i.e., AZ20 and AZD6738) that were sensitive to ATR expression.

ATR holds promise as both a prognostic marker and therapeutic target for KRAS-mutated NSCLC. Our findings may assist in the prediction of prognosis and the development of novel targeted therapies for this disease.