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

TL;DR

This study explores how gene expression in metastatic kidney cancer changes with different treatments in mice, suggesting that treatment choices should adapt based on these changes to improve patient outcomes.

Contribution

The study reveals treatment-specific gene expression changes in metastatic renal cell carcinoma using a syngeneic mouse model, offering insights for personalized sequential therapies.

Findings

Monotherapy upregulates the fibroblast growth factor pathway in metastatic tumors.

Combination therapy activates the mTOR pathway in metastatic tumors.

Treatment-specific gene expression changes influence response to subsequent therapies.

Abstract

Although targeted therapies and immune checkpoint inhibitors have improved patient outcomes, most metastatic renal cell carcinoma tumors eventually become resistant to treatment and progress. In this study, we used a syngeneic mouse model of metastatic renal cell carcinoma to investigate how gene expression changes during disease progression and in response to treatment with cabozantinib, an anti-PD-1 antibody, or both. We found that different treatments activated distinct molecular pathways in metastatic tumors. These treatment-specific changes influenced how tumors responded to subsequent therapies. Our findings suggest that the biology of metastatic renal cell carcinoma evolves depending on prior treatment, and that selecting second-line therapies based on these molecular changes may improve outcomes. This research provides insights that could help guide future treatment strategies and support the development of more effective, personalized therapy sequences for patients with metastatic renal cell carcinoma.

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.

Figures