Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma - PubMed
Source : https://pubmed.ncbi.nlm.nih.gov/36719376/
Bruton's tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while ...
Conclusions: We conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.
• Source: The Journal of Clinical Investigation
• Conclusions “We conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.”
• In the current preclinical study, U.S. researchers observed that MALT1 was overexpressed in IBN-resistant (IBN-R) MCL cells.
• “Genetic knockout (KO) or pharmacological inhibition revealed that MALT1, but not CARD11, drives BTKi resistance via bypassing upstream BTK/CARD11 signaling. Unbiased transcriptome and protein profiling revealed that MALT1 inhibition potently suppressed NF-κB, PI3K/AKT/mTOR, and integrin signaling, and diminished MCL cell proliferation and dissemination. Importantly, combinatorial treatment with MALT1 inhibitors (e.g., MI-2 and safimaltib) and BTKis (e.g., IBN and PBN) produced potent anti-MCL activity in both IBN-R MCL cell lines and patient-derived xenograft (PDX) models. ” they wrote.
• MALT lymphoma represents the most frequent extranodal subtype of NHL, with the chromosomal translocation t(11;18) (q21:q21) characteristic of this subtype. MALT lymphoma leads to the expression of an API2-MALT1 fusion oncoprotein, which contains the N-terminus of API2 and the C-terminus of MALT1 (immunoglobulin-like domains and caspase-like domain).