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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic
Benoit Beuselinck1, Sylvie Job2, Etienne Becht3
1Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France. Labex Immuno-oncology, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Oncology, Paris, France.
Purpose:
Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib.
Experimental Design:
We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel-Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib.
Results:
Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands.
Conclusions:
ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs.
Insights
Molecular subtypes of clear-cell renal cell carcinoma (ccRCC) predict response to sunitinib treatment in metastatic patients. These subtypes can guide personalized therapy with targeted tyrosine kinase inhibitors (TKIs) or other agents.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) for targeted tyrosine kinase inhibitor (TKI) therapy, such as sunitinib, remains challenging.
- Identifying predictive molecular markers is crucial for optimizing treatment strategies in m-ccRCC.
Purpose of the Study:
- To identify molecular markers associated with treatment outcomes in m-ccRCC patients receiving sunitinib.
- To explore the relationship between ccRCC molecular subtypes and response to sunitinib.
Main Methods:
- Global transcriptome analysis of 53 primary ccRCC tumors from patients who developed metastatic disease and received sunitinib.
- Analysis of chromosome copy-number aberrations, methylation status, and gene mutations (VHL, PBRM1).
- Validation in an independent cohort of 47 ccRCC samples.
Main Results:
- Four robust ccRCC molecular subtypes (ccrcc1-4) were identified, showing differential responses to sunitinib.
- Subtypes ccrcc1/ccrcc4 exhibited lower response rates, progression-free survival, and overall survival compared to ccrcc2/ccrcc3.
- These subtypes were significant predictors in multivariate analysis for PFS and OS; ccrcc1/ccrcc4 showed stem-cell signatures and hypermethylation, while ccrcc4 had sarcomatoid features and an immune-suppressive microenvironment.
Conclusions:
- ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients.
- These subtypes may serve as biomarkers for personalized treatment selection in mRCC.
- Potential for utilizing TKIs, demethylating agents, or immunomodulatory drugs based on identified subtypes.
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