TitleMALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.
Publication TypeJournal Article
Year of Publication2017
AuthorsSaba, Nakhle S., Wong Deanna H., Tanios Georges, Iyer Jessica R., Lobelle-Rich Patricia, Dadashian Eman L., Liu Delong, Fontan Lorena, Flemington Erik K., Nichols Cydney M., Underbayev Chingiz, Safah Hana, Melnick Ari, Wiestner Adrian, and Herman Sarah E. M.
JournalCancer Res
Volume77
Issue24
Pagination7038-7048
Date Published2017 12 15
ISSN1538-7445
KeywordsAdenine, Apoptosis, B-Lymphocytes, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Neoadjuvant Therapy, Piperidines, Protein Kinase Inhibitors, Pyrazoles, Pyrimidines, Treatment Outcome
Abstract

<p>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 or , 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 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 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. .</p>

DOI10.1158/0008-5472.CAN-17-2485
Alternate JournalCancer Res
PubMed ID28993409
PubMed Central IDPMC5732856
Grant ListR01 CA187492 / CA / NCI NIH HHS / United States
R01 AI106676 / AI / NIAID NIH HHS / United States
Z01 HL002346-04 / ImNIH / Intramural NIH HHS / United States
Z99 HL999999 / ImNIH / Intramural NIH HHS / United States
P01 CA214091 / CA / NCI NIH HHS / United States
ZIA HL002346-12 / ImNIH / Intramural NIH HHS / United States
U54 GM104940 / GM / NIGMS NIH HHS / United States
ZIA HL002346 / ImNIH / Intramural NIH HHS / United States