Professor of Medicine University at Buffalo Buffalo, NY, United States
Background: TFE3 is a member of the basic helix-loop-helix leucine zipper MiT transcription factor family and its chimeric proteins are associated with translocation renal cell carcinoma (tRCC). Despite the variety of genes fusions, most of TFE3 fusions partner genes are related to spliceosome machinery. Dissecting the function of TFE3 fused to spliceosome machinery factors (TFE3-SF) could direct the development of effective therapies for this lethal disease, which is refractory to standard treatments for kidney cancer.
Methods: Here, by using a combination of in silico structure prediction, transcriptome profiling, molecular characterization, and high-throughput high-content screening (HTHCS) we interrogated a number of oncogenic mechanisms of TFE3-SF-containing fusions. Using HTHCS combined with FRET technology, we screened the FDA approved drugs library LOPAC and a small molecule library (Microsource) and identified compounds that inhibit TFE3-SF dimerization. Hit compounds were validated in 2D and 3D models utilizing patient derived xenolines and xenografts expressing TFE3-SF
Results: The antihistamine terfenadine demonstrated decreased TFE3 dimerization and nuclear expression in different models of tRCC. This was associated with decreased cell proliferation and reduced in vivo tumor growth. Interestingly, we observed a synergistic interaction with the receptor tyrosine kinase inhibitor sunitinib and a decreased lysosomal sequestration of this drug.
Conclusions: The antihistamine terfenadine showed target modulation and antitumor activity. Overall, our results unmask synthetic vulnerabilities of TFE3-SF dimerization for novel therapeutic strategies in patients with this aggressive type of kidney cancer.
