Do mantle cell lymphomas have an ‘Achilles heel’?

Abstract

Purpose of review Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this manuscript we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting. Recent findings In addition to Cyclin-D1 the transcription factor SOX-11 emerged as a common characteristic of MCL. Genomic studies have identified a number of recurrently mutated genes; in order of descending frequency these include ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1/2 and TRAF2. However, no clear oncogenic driver has been identified. In contrast, several observations indicate that MCL cells are antigen-experienced cells and that the tumor microenvironment and B-cell receptor engagement are important. This is underscored by the impressive clinical responses achieved with the BTK inhibitor ibrutinib. Recently identified activating mutations in the non-canonical NF-κB pathway could give rise to ibrutinib resistance. PARP and aurora kinase inhibitors may be synthetic lethal with the common aberrations in DNA damage pathways found in MCL. Also, ABT-199, a potent and selective inhibitor of BCL-2 has promising activity in early studies. Summary MCL is a heterogeneous disease and no single Achilles heel has been identified. Nevertheless, genomic, molecular, and clinical studies have revealed vulnerabilities that can be exploited for effective therapy.

Molecular Evidence for Antigen Drive in the Natural History of Mantle Cell Lymphoma

“…The fact that different tissues express varying levels of AID isoform mRNA indicates that the microenvironment may be a critical factor for shaping clonal behavior and implies that malignant B cells may behave differently depending on their location. 36 Examination of AID mRNA isoform expression within different tissue specimens (preferably LN and PB) from the same patient and time point would be highly informative; however, such samples were lacking. In addition, it should be taken into account that the analysis was conducted on whole-tissue samples and not on purified tumor cells.…”

Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma

“…Based on high response rates in a phase 2 clinical data, ibrutinib was recently approved by the FDA for the treatment of MCL [ 21 ]. However, approximately one third of patients did not respond and some became resistant to ibrutinib during treatment [ 21 , 27 , 28 ]. Because ABT-199 kills MCL cells through a distinct mechanism of action and is particularly potent against peripheral MCL cells mobilized by ibrutinib, these agents could be highly complementary and beneficial to patients with significant unmet medical need.…”

SOX11 promotes tumor protective microenvironment interactions through CXCR4 and FAK regulation in mantle cell lymphoma

“…Although the mechanisms and signaling pathways of this tumorigenic event in MCL are poorly understood, [13][14][15] promising therapeutic approaches that disrupt crosstalk between the microenvironment and tumor cells to prevent the development of drug resistance and chemotherapy refractoriness are currently in early clinical development in patients with MCL. [16][17][18][19][20][21] In this study, we searched for potential SOX11 direct target genes that may explain the relationship between SOX11 and tumor microenvironment protective interactions to find new…”