Treatment-Induced Gene Expression Changes in Metastatic Renal Cell Carcinoma: Insights from a Syngeneic Mouse Model

This study aimed to clarify the alterations in gene expression in metastatic renal cell carcinoma (mRCC) during disease progression and in response to treatment with immune checkpoint inhibitors using a syngeneic mouse mRCC model. RENCA cells were orthotopically implanted in BALB/c mice. Mice received first-line treatment with cabozantinib, anti-PD-1 antibody, or a combination. Tumor progression was monitored using serial micro- computed tomography. Lung metastasis samples were collected, and RNA sequencing was performed. Mice with apparent disease progression received second-line treatment with axitinib, everolimus, or lenvatinib after combination therapy. The median overall survival was 28, 34, 34, and 49 days in untreated mice and those treated with cabozantinib, anti-PD-1, or their combination, respectively (p < 0.05). RNA sequencing revealed upregulation of the fibroblast growth factor pathway in lung metastases after monotherapy, whereas mTOR pathway activation was observed only after combination therapy. Treatment-specific gene expression changes occur in mRCC, suggesting that the optimal target for sequential therapy in mRCC varies depending on prior treatment. Overall design: This submission includes RNA sequencing data from lung metastases of a syngeneic mouse metastatic renal cell carcinoma model. RENCA cells were orthotopically implanted into BALB/c mice. Experimental groups include untreated controls and treatment groups receiving cabozantinib, anti-PD-1 antibody, or their combination as first-line therapy. Second-line treatment groups include axitinib, everolimus, or lenvatinib administered after combination therapy. The study investigates treatment-induced gene expression changes to evaluate molecular alterations and potential targets for sequential therapy. Each treatment group included biological replicates. Control samples (untreated) are included for comparison.