Tipping the balance: toward rational combination therapies to overcome venetoclax resistance in mantle cell lymphoma.

Autor: Thus YJ; Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands., Eldering E; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands.; Department of Experimental Immunology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands.; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands., Kater AP; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands.; Department of Hematology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands., Spaargaren M; Department of Pathology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.; Cancer Center Amsterdam (CCA), Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands. marcel.spaargaren@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2022 Sep; Vol. 36 (9), pp. 2165-2176. Date of Electronic Publication: 2022 Jun 20.
DOI: 10.1038/s41375-022-01627-9
Abstrakt: Mantle cell lymphoma (MCL), an aggressive, but incurable B-cell lymphoma, is genetically characterized by the t(11;14) translocation, resulting in the overexpression of Cyclin D1. In addition, deregulation of the B-cell lymphoma-2 (BCL-2) family proteins BCL-2, B-cell lymphoma-extra large (BCL-X L ), and myeloid cell leukemia-1 (MCL-1) is highly common in MCL. This renders these BCL-2 family members attractive targets for therapy; indeed, the BCL-2 inhibitor venetoclax (ABT-199), which already received FDA approval for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), shows promising results in early clinical trials for MCL. However, a significant subset of patients show primary resistance or will develop resistance upon prolonged treatment. Here, we describe the underlying mechanisms of venetoclax resistance in MCL, such as upregulation of BCL-X L or MCL-1, and the recent (clinical) progress in the development of inhibitors for these BCL-2 family members, followed by the transcriptional and (post-)translational (dys)regulation of the BCL-2 family proteins, including the role of the lymphoid organ microenvironment. Based upon these insights, we discuss how rational combinations of venetoclax with other therapies can be exploited to prevent or overcome venetoclax resistance and improve MCL patient outcome.
(© 2022. The Author(s).)
Databáze: MEDLINE
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