Dataset Information

Exceptional Response to BTK Inhibitors in Aggressive Lymphomas Linked to Chronic Selective Autophagy

ABSTRACT: Diffuse large B cell lymphoma is an aggressive cancer type that is profoundly heterogeneous, both molecularly and phenotypically, presenting a challenge for precision medicine. Inhibitors of the kinase BTK block B cell receptor (BCR)-dependent NF-ï«B signaling and are particularly effective in certain molecular subtypes of DLBCL, but the underlying mechanisms are poorly understood. The MCD genetic subtype, which often acquires mutations targeting the BCR subunit CD79B and MYD88, typically resists chemotherapy but responds exceptionally to BTK inhibitors. By functional proteogenomics, we discovered a non-canonical form of chronic active selective autophagy in MCD DLBCL that targets ubiquitinated mutant MYD88, an adaptor protein essential for oncogenic NF-ï«B survival signaling, for degradation. Moreover, MCD tumors acquire genetic and epigenetic alterations that attenuate this novel tumor suppressive pathway. Importantly, BTK inhibitors activated this chronic selective autophagy pathway to degrade MYD88, thus explaining the exceptional benefit of BTK-targeted therapies in the MCD DLBCL subtype.

INSTRUMENT(S): Orbitrap Fusion, Orbitrap Exploris 480, Q Exactive HF, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Culture

DISEASE(S): Diffuse Large B-cell Lymphoma

SUBMITTER: Sebastian Scheich

LAB HEAD: Louis M. Staudt

PROVIDER: PXD041092 | Pride | 2025-05-06

REPOSITORIES: Pride

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Publications

Response to Bruton's tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy.

Phelan James D JD Scheich Sebastian S Choi Jaewoo J Wright George W GW Häupl Björn B Young Ryan M RM Rieke Sara A SA Pape Martine M Ji Yanlong Y Urlaub Henning H Bolomsky Arnold A Doebele Carmen C Zindel Alena A Wotapek Tanja T Kasbekar Monica M Collinge Brett B Huang Da Wei DW Coulibaly Zana A ZA Morris Vivian M VM Zhuang Xiaoxuan X Enssle Julius C JC Yu Xin X Xu Weihong W Yang Yandan Y Zhao Hong H Wang Zhuo Z Tran Andy D AD Shoemaker Christopher J CJ Shevchenko Galina G Hodson Daniel J DJ Shaffer Arthur L AL Staudt Louis M LM Oellerich Thomas T

Cancer cell 20240111 2

Diffuse large B cell lymphoma (DLBCL) is an aggressive, profoundly heterogeneous cancer, presenting a challenge for precision medicine. Bruton's tyrosine kinase (BTK) inhibitors block B cell receptor (BCR) signaling and are particularly effective in certain molecular subtypes of DLBCL that rely on chronic active BCR signaling to promote oncogenic NF-κB. The MCD genetic subtype, which often acquires mutations in the BCR subunit, CD79B, and in the innate immune adapter, MYD88<sup>L265P</sup>, typi ...[more]

PMID: 38215749

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Project description:Pathologic activation of the Toll-like receptor (TLR) pathway underlies various human disorders such as autoimmune diseases, chronic inflammatory diseases and lymphoid malignancies. Current therapy of these diseases relies on immunosuppressive or chemotherapeutic agents, but more effective therapeutics tailored to disease-causing mechanisms are needed. Pivotal to TLR signaling is the IL-1 receptor-associated kinase 4 (IRAK4), which is recruited to TLRs by the adaptor protein MyD88. Recruitment of IRAK kinases to MyD88, triggers the formation of a signaling competent myddosome complex, which underlies the pathogenesis of many immuno-inflammatory disorders, suggesting that IRAK4 inhibitors might be useful in the treatment of these diseases. Gain-of-function MYD88 mutations activate IRAK4 in several mature B cell malignancies, including activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). Development of selective IRAK4 inhibitors has been confounded by the challenging structure of the IRAK4 catalytic domain. Using structure-based drug design methodologies, we identified potent and selective IRAK4 inhibitors. These small molecules suppress LPS-induced TNFalpha production in vitro and in vivo, and are efficacious in mouse models of collagen-induced arthritis and MyD88-dependent inflammatory gout. Human ABC DLBCL cell lines that harbor the activating, oncogenic MyD88 L265P mutation are killed by IRAK4 inhibitors, both in vitro and in mouse xenograft models. IRAK4 inhibitors synergize with the BTK inhibitor ibrutinib, with the Syk inhibitor PRT062607, and with the Bcl-2 inhibitor ABT-199 in killing ABC DLBCL cells, suggesting new therapeutic strategies for this refractory cancer. Four ABC DLBCL cell lines (OCI-Ly10, TMD8, HBL1 and OCI-Ly3), were treated with either ND-2158 or the structurally related negative control compound ND-1659 for 6, 12, 24 or 36 h in culture. Gene expression profiling was performed using two-color human Agilent 4x44K gene expression arrays comparing signal from control compound-treated (ND-1659) control cells (Cy3), toÂ cells treated with ND-2158 for the indicated times (Cy5).

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