Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

CAYROL, FLORENCIA; REVUELTA, MARIA V.; DEBERNARDI, MERCEDES; PAULAZO, ALEJANDRA; PHILLIP, JUDE M.; ZAMPONI, NAHUEL; STERLE, HELENA; DÍAZ FLAQUÉ, MARÍA C.; MAGRO, CYNTHIA; MARULLO, ROSSELLA; MULVEY, ERIN; RUAN, JIA; CREMASCHI, GRACIELA A.; CERCHIETTI, LEANDRO

MOLECULAR CANCER THERAPEUTICS

AMER ASSOC CANCER RESEARCH

Año: 2022 vol. 21 p. 1485 - 1496

1535-7163

Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because 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 preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVβ3 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. Teaser: Inhibiting aVb3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.F. Cayrol and M.V. Revuelta are the co-first authors of this article. G.A. Cremaschi and L. Cerchietti are the co-senior authors of this article.