TY - JOUR
T1 - Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma
AU - Cayrol, Florencia
AU - Revuelta, Maria V.
AU - Debernardi, Mercedes
AU - Paulazo, Alejandra
AU - Phillip, Jude M.
AU - Zamponi, Nahuel
AU - Sterle, Helena
AU - Flaqué, María C.Díaz
AU - Magro, Cynthia
AU - Marullo, Rossella
AU - Mulvey, Erin
AU - Ruan, Jia
AU - Cremaschi, Graciela A.
AU - Cerchietti, Leandro
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-22-0093
DO - 10.1158/1535-7163.MCT-22-0093
M3 - Article
C2 - 35793463
AN - SCOPUS:85137675329
SN - 1535-7163
VL - 21
SP - 1485
EP - 1496
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -