Objective Patient-derived xenografts models (PDX) have made a recent comeback in popularity.These models, established by direct implants of clinical cancer tissue fragments in immunodeficient mice, have great potential in drug development studies because they faithfully reproduce the patients original tumor for both immunohistochemical markers and genetic alterations as well as in terms of response to common therapeutics.They also maintain the original tumor heterogeneity, allowing studies of specific cellular subpopulations.A subpopulation of tumor cells, termed cancer stem cells (CSC), appears uniquely able to fuel the growth of phenotypically and histologically diverse tumors.It has been proposed, therefore, that failure to effectively treat cancer may in part be due to preferential resistance of these CSC to chemotherapeutic agents.Methods We used a PDX model of renal cell carcinoma (RCC) and a two stage approach was used to test the hypotheses that targeting CSC could increase the efficacy of tyrosine kinase inhibitors (TKIs).PDX model from a sorafenib-resistant patient tissue was treated with sorafenib first, and randomized, after tumor regression to continuing treatment with sorafenib, a hedgehog inhibitor alone or in combination with sorafenib.We tested markers associated with CSC such as CD105, CD133, CD44, CXCR4, and the hedgehog pathway.Results After treatment with sorafenib, CSC were enriched in renal cell carcinoma tumors and remain capable of rapidly regenerating tumors from which they originated.Meantime, treated tumor showed an enrichment in CSC markers such as CD 105, CD 133.Combined treatment with sorafenib and cyclopamine induced tumor regression and decrease in CSC markers and hedgehog signaling.Cytoplasmic CD24 and CXCR4 were inversely and strongly associated with growth and were expressed in a minority of cells that we propose constitute the CSC compartment.Conclusion Hedgehog inhibitors as part of a dual compartment therapeutic approach were able to further reduce tumor growth and decreased both static and dynamic markers of CSC.Furthermore hedgehog inhibitors could reverse the drug-resistance of the cancer stem cells, indicating that drug-resistance of the cancer stem cells to TKIs was asscociated with hedgehog pathway.And PDX models are a valid platform to test multicompartment therapeutic approaches in cancer stem cells of renal cell carcinoma (RCC).