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

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

  • Cancer Cell. 2024 Jan 6:S1535-6108(23)00447-6. doi: 10.1016/j.ccell.2023.12.019.
James D Phelan 1,  Sebastian Scheich 2,  Jaewoo Choi 1,  George W Wright 3,  Björn Häupl 4,  Ryan M Young 1,  Sara A Rieke 5,  Martine Pape 4,  Yanlong Ji 6,  Henning Urlaub 7,  Arnold Bolomsky 1,  Carmen Doebele 8,  Alena Zindel 4,  Tanja Wotapek 5,  Monica Kasbekar 1,  Brett Collinge 9,  Da Wei Huang 1,  Zana A Coulibaly 1,  Vivian M Morris 10,  Xiaoxuan Zhuang 1,  Julius C Enssle 8,  Xin Yu 1,  Weihong Xu 1,  Yandan Yang 1,  Hong Zhao 1,  Zhuo Wang 1,  Andy D Tran 11,  Christopher J Shoemaker 12,  Galina Shevchenko 13,  Daniel J Hodson 13,  Arthur L Shaffer 3rd 1,  Louis M Staudt 14,  Thomas Oellerich 15
Affiliations

Affiliations

  • 1 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Goethe University Frankfurt, University Hospital, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany; University Cancer Center (UCT) Frankfurt, University Hospital, Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany.
  • 3 Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, Bethesda, MD 20850, USA.
  • 4 Goethe University Frankfurt, University Hospital, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany.
  • 5 Goethe University Frankfurt, University Hospital, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany.
  • 6 Goethe University Frankfurt, University Hospital, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany; Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany; Bioanalytics, Institute of Clinical Chemistry, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
  • 7 Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, Am Fassberg 11, 37077 Göttingen, Germany; Bioanalytics, Institute of Clinical Chemistry, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
  • 8 Goethe University Frankfurt, University Hospital, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany; University Cancer Center (UCT) Frankfurt, University Hospital, Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany.
  • 9 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC V5Z 4E6, Canada.
  • 10 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Johns Hopkins University Department of Biology, 3400 N. Charles Street, Baltimore, MD 21218, USA.
  • 11 CCR Microscopy Core, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 12 Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
  • 13 Wellcome-MRC Cambridge Stem Cell Institute, Cambridge Biomedical Campus, Cambridge CB2 0AW, UK.
  • 14 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: [email protected].
  • 15 Goethe University Frankfurt, University Hospital, 60590 Frankfurt am Main, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, 60528 Frankfurt am Main, Germany; University Cancer Center (UCT) Frankfurt, University Hospital, Goethe University, 60590 Frankfurt am Main, Germany; Frankfurt Cancer Institute, Goethe University, 60596 Frankfurt am Main, Germany. Electronic address: [email protected].
PMID: 38215749 DOI: 10.1016/j.ccell.2023.12.019
Abstract

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, MyD88L265P, typically resists chemotherapy but responds exceptionally to Btk inhibitors. However, the underlying mechanisms of response to Btk inhibitors are poorly understood. Herein, we find a non-canonical form of chronic selective Autophagy in MCD DLBCL that targets ubiquitinated MyD88L265P for degradation in a TBK1-dependent manner. MCD tumors acquire genetic and epigenetic alterations that attenuate this autophagic tumor suppressive pathway. In contrast, Btk inhibitors promote autophagic degradation of MyD88L265P, thus explaining their exceptional clinical benefit in MCD DLBCL.

Keywords

Bruton’s tyrosine kinase; DLBCL; autophagy; functional genomics; proteomics; targeted therapy.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15473
    99.76%, IKKβ Inhibitor
    IKK