Abstract 7580: The antihistamine terfenadine inhibits TFE3 dimerization, has antitumor activity and synergizes with tyrosine kinase inhibitors in translocation renal cell carcinoma

Abstract Translocation renal cell carcinoma is a subtype of kidney cancer characterized by gene fusions involving MiT transcription factor family, TFE3 and TFEB, with various gene partners. In general, these tumors do not respond to conventional therapies, which stresses the importance of developing new therapeutical approaches. To date, several TFE3 fusion gene partners have been identified. However, the mechanism driving TFE3 cooperation with various gene partners remains to be elucidated. We have previously shown the vulnerability of dimerization domain of multiple TFE3-fusion proteins, and we have screened the FDA approved drugs library LOPAC and a small molecule library (Microsource) to identify compounds that inhibit TFE3 dimerization. The antihistamine terfenadine was found to inhibit TFE3 dimerization and had antiproliferative activity in different models of tRCC, both in vitro and in vivo. Interestingly, our more recent data show that terfenadine reduced the amount of TFE3 in the nuclei. We have also observed enhanced antiproliferative activity of terfenadine in HEK293 cells overexpressing PRCC-TFE3, SPFQ-TFE3 or NONO-TFE3 compared to TFE3 alone or vector control, suggesting a targeted effect of terfenadine on cells driven by these TFE3-SF fusions. In addition, knock-down of SFPQ-TFE3 in HEK293 partially reversed this enhanced sensitivity to terfenadine. Cell proliferation and combination index analysis were performed in cell lines endogenously expressing the most common TFE3-fusion proteins cells to determinate the combination with different tyrosine kinase inhibitors. Immunofluorescence and confocal microscopy were performed to assess the impact on TFE3 fusion protein levels. The combination of terfenadine with sunitinib showed a synergistic effect in cells endogenously expressing PRCC-TFE3 (IC50=1.5µM; Fraction Affected > 0.05) and NONO-TFE3 (IC50=1.8µM; Fraction Affected<0.7) fusions. The combination of terfenadine with crizotinib showed a synergistic effect in cells expressing SFPQ-TFE3 fusion (IC50=0.7µM; Fraction Affected>0.7). The combination of terfenadine with dovitinib showed a synergistic effect in cells expressing PRCC-TFE3 fusion (IC50=1µM; Fraction Affected>0.4). These preliminary data suggest a different response to the combination with different TKIs. This observation underlines the importance of identifying the TFE3 partner gene for targeted therapy. Overall, our results suggest that targeting the dimerization domain along with different oncogenic pathways activated in tRCC cells may represent a new therapeutic approach for this disease. Citation Format: Ilaria Delle Fontane, Ricardo Cordova, Christopher Rupert, Sabrina Orsi, Abbas Jawadwala, David E. Heppener, Roberto Pili. The antihistamine terfenadine inhibits TFE3 dimerization, has antitumor activity and synergizes with tyrosine kinase inhibitors in translocation renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7580.