Inhibition of the integrin alpha-V beta-3 reverts the paradoxical effect of levothyroxine replacement during bexarotene therapy in cutaneous T-cell lymphoma (CTCL)

CAYROL F; DEBERNARDI MM; REVUELTA MV; PAULAZO A; STERLE HA; DIAZ FLAQUE MARIA MC; ROSEMBLIT C; CERCHIETTI LC; CREMASCHI GA

Congreso; Reunión Anual SAIC; 2018

Bexarotene (Bex), a RXR agonist used for the treatment of CTCL, is associated with hypothyroidism, thus patients required the concomitant administration of levothyroxine (T4). We found that physiological levels of TH contribute to the malingnat phenotype of CTCL by activating TH membrane receptor, integrin V3 (mTR). Hereon we investigated the consequence of T4 administration to the antineoplastic effect of bexarotene in CTCL.We conducted RNA-sequencing and qPCR assays in Bex-treated HuT78 cells and found that bexarotene induces transcriptional changes in genes related to cell proliferation and chemotaxis, as well as immunity and interferon response. This suggests that Bex treatment could also impact in antitumor immunity. In TH-depleted culture conditions we observed a higher effect of Bex on CTCL viability and apoptosis. As hypothyroidism is associated with marked immunosuppression, favouring CTCL progression, we determined the impact of TH replacement on Bex using EL4 murine TCL model. We treated tumor-bearing mice, with vehicle (Veh), Bex and Bex with T4 (BexT4+) and found that Bex decreased tumor growth; being the effect significantly higher in the absence of T4 replacement (p