Mechanistic insights into the differential effects of thalidomide and lenalidomide in metastatic prostate cancer.

AIM: To understand why thalidomide and lenalidomide exhibit different responses in metastatic prostate cancer (mPCa) treatment. METHODS: We analyzed the perturbation signatures of thalidomide, lenalidomide, flutamide treated mPCa cell line from Library of Integrated Network-based Cellular Signatures database and transcriptome of docetaxel-treated mPCa patients. RESULTS: Flutamide and docetaxel downregulated 'Steroid Biosynthesis', 'Cell cycle' and PCa specific transcription factor networks. Thalidomide inhibited 'Cell cycle' and 'E2F network', possibly accounting for its synergistic effects with docetaxel. Conversely, lenalidomide promoted 'Cell cycle' and 'Cholesterol biosynthesis'. CONCLUSION: Hence, we propose that lenalidomide upregulates cholesterol synthesis followed by enhanced rate of cell cycle, thereby nurturing a hyperproliferative tumor microenvironment. In summary, this study offers a possible explanation for the differential outcomes in the treatment of mPCa with thalidomide and lenalidomide.