MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia

Abstract

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.

Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth

“…MALT1 is required for the survival of ABC DLBCLs, other types of lymphomas such as mantle cell lymphoma (46), primary effusion lymphoma (47), and chronic Lymphocytic leukemia (48), and potentially other tumors, hence, there is great interest in developing potent inhibitors for this target. MALT1 is part of the CBM complex, which is central to BCR activation.…”

Germinal center‐derived lymphomas: The darkest side of humoral immunity

“…[206][207][208][209] MALT1 is a key mediator of the BCR signaling to NF-κB and is essential in the development of ABC-DLBCL and other lymphomas including mantle cell lymphoma, primary effusion lymphoma, and chronic lymphocytic leukemia (CLL). 136,[210][211][212][213][214] Moreover, MALT1 inhibition was shown to be effective in CLL patients, even those with mutations of BTK, PLCy, and CARD11 that cause Ibrutinib resistance. 214 Regarding TLR signaling, IRAK4 inhibitors show activity in preclinical studies in ABC-DLBCL cell lines 144 and PDXs.…”

“…136,[210][211][212][213][214] Moreover, MALT1 inhibition was shown to be effective in CLL patients, even those with mutations of BTK, PLCy, and CARD11 that cause Ibrutinib resistance. 214 Regarding TLR signaling, IRAK4 inhibitors show activity in preclinical studies in ABC-DLBCL cell lines 144 and PDXs. 215 A phase 1b clinical trial of one such compound is currently underway.…”

The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-in Mice

“…But, also the other members of the CBM complex are frequently found to be mutated, overexpressed, or affected by chromosomal translocations (MALT1-API2 or c-IAP2-MALT1). The GOF mutations of CBM members promote lymphomagenesis and MALT1 inhibitors have shown to allow for new treatment options for patients with refractory t(11;18)-positive MALT1 lymphoma [ 85 , 86 , 87 ]. The constitutively active CBM complex leads to constant activation of NF-κB and also to the permanent induction of the JNK/AP1 pathway and expression of RNA-binding proteins (Roquin-1 and -2, Regnase-1), which mediate the stabilization of several NF-κB-dependent transcripts.…”