Inhibition of integrin AlphaVBeta3 signaling improves the antineoplastic effect of bexarotene in cutaneous T-cell lymphoma

CAYROL F; VICTORIA REVUELTA; MERCEDES DEBERNARDI; PAULAZO ALEJANDRA; PHILLIP J; ZAMPONI N; STERLE HA; DIAZ FLAQUE MARIA CELESTE; MAGRO C; MARULLO R; MULVEY E; RUAN J; CREMASCHI GA; CERCHIETTI LC

MOLECULAR CANCER THERAPEUTICS

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2022

1535-7163

Bexarotene is a specific RXR agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Since bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVβ3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an αVβ3 -dependent manner, the antineoplastic effect of bexarotene; levothyroxine supplementation in pre-clinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVβ3 3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin αVβ3 inhibitors as part of CTCL regimens based on bexarotene administration.