|Title||Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Fontan L, Goldstein R, Casalena G, Durant M, Teater MR, Wilson J, Phillip J, Xia M, Shah S, Us I, Shinglot H, Singh A, Inghirami G, Melnick A|
|Date Published||2021 02 11|
|Keywords||Animals, Antineoplastic Agents, Drug Design, Drug Resistance, Neoplasm, Drug Synergism, Feedback, Physiological, Female, Humans, Lymphoma, Large B-Cell, Diffuse, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred NOD, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Neoplasm Proteins, Organoids, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Processing, Post-Translational, Receptors, Antigen, B-Cell, Ribosomal Protein S6 Kinases, RNA, Small Interfering, Signal Transduction, Toll-Like Receptors, Xenograft Model Antitumor Assays|
MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction-targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway-targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy.
|PubMed Central ID||PMC7885826|
|Grant List||R35 CA220499 / CA / NCI NIH HHS / United States |
R01 CA238745 / CA / NCI NIH HHS / United States
P01 CA229100 / CA / NCI NIH HHS / United States
P50 CA192937 / CA / NCI NIH HHS / United States
R01 AI132738 / AI / NIAID NIH HHS / United States
R33 CA212968 / CA / NCI NIH HHS / United States
Giorgio Inghirami, M.D.