Management of Drug Resistance in Mantle Cell Lymphoma

Abstract

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell hemopathy characterized by the translocation t(11;14)(q13;q32) that leads to the overexpression of the cell cycle regulatory protein cyclin D1. This translocation is the initial event of the lymphomagenesis, but tumor cells can acquire additional alterations allowing the progression of the disease with a more aggressive phenotype and a tight dependency on microenvironment signaling. To date, the chemotherapeutic-based standard care is largely inefficient and despite the recent advent of different targeted therapies including proteasome inhibitors, immunomodulatory drugs, tyrosine kinase inhibitors, relapses are frequent and are generally related to a dismal prognosis. As a result, MCL remains an incurable disease. In this review, we will present the molecular mechanisms of drug resistance learned from both preclinical and clinical experiences in MCL, detailing the main tumor intrinsic processes and signaling pathways associated to therapeutic drug escape. We will also discuss the possibility to counteract the acquisition of drug refractoriness through the design of more efficient strategies, with an emphasis on the most recent combination approaches.

Mcl‐1 and Bcl‐xL levels predict responsiveness to dual MEK/Bcl‐2 inhibition in B‐cell malignancies

“…The introduction of targeted therapies has greatly improved the management of hematological malignancies. Still, development of treatment resistance remains an unresolved challenge, stressing the need for novel drug targets and combinatorial approaches [ 1 , 2 , 3 ]. Direct drug testing of a patient’s tumor cells can identify effective therapies, including novel agents and combinations [ 4 ].…”

Relapsed Mantle Cell Lymphoma, Allogenic Stem Cell Transplantation and COVID-19

“…Allo-SCT results in a prolonged remission/cure in up to 40% of chemo-resistant MCL; the value of combining BCL2 mimetic therapy with graft versus lymphoma effect has resulted in a CR in this patient despite a post-allograft progression [4,12]. The recent publication indicating that Chimeric Antigen Receptor T-Cell (CAR-T) therapy may provide an effective and less immunosuppressive approach for MCL is welcome [14].…”

“…Ara-C (Cytarabine) containing induction treatment and high dose consolidation with BEAM (Carmustine, Etoposide, Cytarabine and Melphalan) is the standard of care for fit patients with Mantle Cell Lymphoma (MCL) resulting in survivals of 65-75% at 5 years [1,6] and 64% at 10 years [3]. Patients with chemo-refractory disease have a poor prognosis, are candidates for allogenic stem cell transplantation (allo-SCT) [12] and can be bridged to SCT with either targeted therapy (BTK-inhibitor or BCL2-mimetic) or alternative chemo-immunotherapy. Chemo-refractory patients are more likely to have pleomorphic or blastoid MCL often in the context of a TP53 mutation.…”

Constitutive Activation of p62/Sequestosome-1-Mediated Proteaphagy Regulates Proteolysis and Impairs Cell Death in Bortezomib-Resistant Mantle Cell Lymphoma

“…However, more than half of patients display either an innate resistance or develop resistance along the course of the treatment. The development of new PIs (carfilzomib, ixazomib) has not solved the problem [ 4 ]. BTZ inhibits the proteasome by targeting the β5 subunit of the 20S core particle (CP), thereby impairing degradation of intracellular proteins, including crucial factors regulating cell cycle, tumor progression and apoptosis [ 5 ].…”