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 beenused for the treatment of cutaneous T-cell lymphoma (CTCL).Because bexarotene causes hypothyroidism, it requires theadministration of levothyroxine. However, levothyroxine, inaddition to its ubiquitous nuclear receptors, can activatethe aVb3 integrin that is overexpressed in CTCL, potentiallyinterfering the antineoplastic effect of bexarotene. We thusinvestigated the biological effect of levothyroxine in relationto bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an aVb3-dependent manner, the antineoplasticeffect of bexarotene, levothyroxine supplementation in preclinicalmodels was necessary to avoid suppression of lymphoma immunity.Accordingly, selective genetic and pharmacologic inhibition ofintegrin aVb3 improved the antineoplastic effect of bexaroteneplus levothyroxine replacement while maintaining lymphomaimmunity. Our results provide a mechanistic rationale for clinicaltesting of integrin aVb3 inhibitors as part of CTCL regimens basedon bexarotene administration.Teaser: Inhibiting aVb3 integrin improves the antineoplasticeffect of bexarotene while maintaining lymphoma immunity