Do mantle cell lymphomas have an 'Achilles heel'?

Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this article, we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting.

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 Bruton's tyrosine kinase inhibitor ibrutinib. Recently identified activating mutations in the noncanonical nuclear factor-kappa B pathway could give rise to ibrutinib resistance. Poly-ADP ribose polymerase 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 B-cell lymphoma 2, has promising activity in early studies.

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.