Synergistic Cytotoxicity of Lenalidomide and Dexamethasone in Mantle Cell Lymphoma via Cereblon-dependent Targeting of the IL-6/STAT3/PI3K Axis

EBioMedicine
Jiexian MaYanhui Xie

Abstract

At our center, relapsed mantle cell lymphoma (MCL) can be treated with maintenance therapy composed of consecutive low-dose lenalidomide and short-term, high-dose dexamethasone (LD regimen), which achieves good responses (longer overall survival and progression-free survival) and low toxicity. Cereblon is probably targeted by both lenalidomide and dexamethasone, which leads to synergistic cytotoxicity in MCL by inhibiting the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3), phosphatidylinositol 3-kinase (PI3K)/AKT and AKT2/Forkhead box O3 (FOXO3A)/BCL2-like 11 (BIM) pathways. The two drugs synergistically inhibit the same pathways, but through different sites. Cereblon was found expressed in most of the MCL tissues (91.3% positivity). Moreover, cereblon expression is positively correlated with LD regimen sensitivity: long-term lenalidomide exposure downregulates cereblon and induces multi-drug resistance against lenalidomide, dexamethasone, cytarabine, cisplatin, and methotrexate in vitro. Removal of lenalidomide resensitizes lenalidomide-resistant MCL cells to lenalidomide and dexamethasone. Our work suggests that rotating the LD regimen with other regimens would improve MCL maintenance therapy.

References

Oct 24, 2007·The Journal of Allergy and Clinical Immunology·Raif S GehaUNKNOWN International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee
Jul 9, 2008·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Peter H WiernikThomas M Habermann
Jul 17, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lei WuJ Blake Bartlett
Feb 28, 2009·British Journal of Haematology·Thomas M HabermannJoseph M Tuscano
Dec 21, 2010·Critical Reviews in Oncology/hematology·Andre Goy, Brad Kahl
Jan 14, 2011·Annals of Oncology : Official Journal of the European Society for Medical Oncology·T E WitzigM S Czuczman
Feb 23, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Pasquale Sansone, Jacqueline Bromberg
Jul 5, 2012·Advances in Hematology·Marco Gunnellini, Lorenzo Falchi
Sep 22, 2012·British Journal of Haematology·P McKayUNKNOWN British Committee for Standards in Haematology
Sep 5, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Andre GoyThomas E Witzig
Sep 14, 2013·Annals of Oncology : Official Journal of the European Society for Medical Oncology·P L ZinzaniT E Witzig
Aug 26, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·John P LeonardBruce D Cheson

❮ Previous
Next ❯

Methods Mentioned

BETA
transfection
ELISA
flow cytometry
biopsy
flow
biopsies
ubiquitination

Clinical Trials Mentioned

NCT01035463
NCT01865110
NCT01996865

Software Mentioned

CompuSyn

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

BCL-2 Family Proteins

BLC-2 family proteins are a group that share the same homologous BH domain. They play many different roles including pro-survival signals, mitochondria-mediated apoptosis and removal or damaged cells. They are often regulated by phosphorylation, affecting their catalytic activity. Here is the latest research on BCL-2 family proteins.