2. Academic Validation
  3. Inhibition of Integrin αVβ3 Signaling Improves the Antineoplastic Effect of Bexarotene in Cutaneous T-Cell Lymphoma

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

  • Mol Cancer Ther. 2022 Sep 6;21(9):1485-1496. doi: 10.1158/1535-7163.MCT-22-0093.
Florencia Cayrol  # 1,  Maria V Revuelta  # 2,  Mercedes Debernardi 1,  Alejandra Paulazo 1,  Jude M Phillip 3,  Nahuel Zamponi 2,  Helena Sterle 1,  María C Díaz Flaqué 1,  Cynthia Magro 4,  Rossella Marullo 2,  Erin Mulvey 2,  Jia Ruan 2,  Graciela A Cremaschi  # 1,  Leandro Cerchietti  # 2
Affiliations

Affiliations

  • 1 Laboratorio de Neuroinmunomodulación y Oncología Molecular, Instituto de Investigaciones Biomédicas (BIOMED)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Católica Argentina (UCA), Buenos Aires, Argentina.
  • 2 Department of Medicine, Hematology and Oncology Division, Weill Cornell Medicine, New York, New York.
  • 3 Departments of Biomedical Engineering, Chemical and Biomolecular Engineering, Oncology, Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, Maryland.
  • 4 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
  • # Contributed equally.
PMID: 35793463 DOI: 10.1158/1535-7163.MCT-22-0093
Abstract

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 αVβ3 Integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.

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