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MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.
Saba, Nakhle S; Wong, Deanna H; Tanios, Georges; Iyer, Jessica R; Lobelle-Rich, Patricia; Dadashian, Eman L; Liu, Delong; Fontan, Lorena; Flemington, Erik K; Nichols, Cydney M; Underbayev, Chingiz; Safah, Hana; Melnick, Ari; Wiestner, Adrian; Herman, Sarah E M.
Afiliación
  • Saba NS; Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, Louisiana. Sarah.Herman@nih.gov nsaba@tulane.edu.
  • Wong DH; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Tanios G; Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, Louisiana.
  • Iyer JR; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Lobelle-Rich P; Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, Louisiana.
  • Dadashian EL; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Liu D; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Fontan L; Section of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
  • Flemington EK; Department of Pathology, Tulane University, New Orleans, Louisiana.
  • Nichols CM; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Underbayev C; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Safah H; Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, Louisiana.
  • Melnick A; Section of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
  • Wiestner A; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
  • Herman SEM; Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland. Sarah.Herman@nih.gov nsaba@tulane.edu.
Cancer Res ; 77(24): 7038-7048, 2017 12 15.
Article en En | MEDLINE | ID: mdl-28993409
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Pirimidinas / Leucemia Linfocítica Crónica de Células B / Resistencia a Antineoplásicos / Inhibidores Enzimáticos / Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Res Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Pirazoles / Pirimidinas / Leucemia Linfocítica Crónica de Células B / Resistencia a Antineoplásicos / Inhibidores Enzimáticos / Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Res Año: 2017 Tipo del documento: Article Pais de publicación: Estados Unidos