Integrative topological and longitudinal transcriptomic analyses identify a 14-gene interferon-stimulated module associated with acquired sunitinib resistance in clear cell renal cell carcinoma

Acquired sunitinib resistance poses a major clinical challenge in clear cell renal cell carcinoma (ccRCC). We integrated cross-model transcriptomic analysis of resistant cell lines, multi-algorithm protein-protein interaction screening, longitudinal patient-derived xenograft (PDX) profiling, and clinical ccRCC tissue analysis. This framework prioritized a 14-gene interferon-stimulated module that was concordantly upregulated in A498 and 786-O resistant sublines and showed coordinated activation during the therapeutic escape phase in a PDX model. Pathway enrichment linked the module to type I/II interferon signaling and antiviral defense. In cross-sectional clinical ccRCC tissues without annotated sunitinib treatment histories, the module was also more highly expressed than in normal kidney and displayed altered co-expression patterns. This finding supports disease-associated activation but does not establish resistance specificity. Collectively, the data identify a tumor-cell-intrinsic component associated with acquired sunitinib resistance and temporally aligned with therapeutic escape. Functional perturbation and longitudinal patient studies are required to determine causality and predictive value.