Transient stabilization, rather than inhibition, of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma.

Autor: Harrington CT; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA., Sotillo E; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Stanford Cancer Institute, 265 Campus Dr., Stanford, CA, 94305, USA., Robert A; CNRS UMR 8126, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France., Hayer KE; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Bogusz AM; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA., Psathas J; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; The Janssen Pharmaceutical Companies of Johnson & Johnson, 200 Great Valley Parkway, Malvern, PA, 19355, USA., Yu D; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Noncoding RNA Center, Yangzhou University, 225001, Yangzhou, China., Taylor D; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA., Dang CV; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104, USA., Klein PS; Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA., Hogarty MD; Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Geoerger B; CNRS UMR 8203, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France.; Department of Pediatric and Adolescent Oncology, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France., El-Deiry WS; Department of Pathology and Laboratory Medicine, Brown University Medical School, Providence, RI, 02912, USA., Wiels J; CNRS UMR 8126, Univ Paris-Sud - Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France., Thomas-Tikhonenko A; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. andreit@pennmedicine.upenn.edu.; Cell & Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. andreit@pennmedicine.upenn.edu.; Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. andreit@pennmedicine.upenn.edu.; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. andreit@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2019 Oct; Vol. 33 (10), pp. 2429-2441. Date of Electronic Publication: 2019 Mar 26.
DOI: 10.1038/s41375-019-0454-4
Abstrakt: Therapeutic targeting of initiating oncogenes is the mainstay of precision medicine. Considerable efforts have been expended toward silencing MYC, which drives many human cancers including Burkitt lymphomas (BL). Yet, the effects of MYC silencing on standard-of-care therapies are poorly understood. Here we found that inhibition of MYC transcription renders B-lymphoblastoid cells refractory to chemotherapeutic agents. This suggested that in the context of chemotherapy, stabilization of Myc protein could be more beneficial than its inactivation. We tested this hypothesis by pharmacologically inhibiting glycogen synthase kinase 3β (GSK-3β), which normally targets Myc for proteasomal degradation. We discovered that chemorefractory BL cell lines responded better to doxorubicin and other anti-cancer drugs when Myc was transiently stabilized. In vivo, GSK3 inhibitors (GSK3i) enhanced doxorubicin-induced apoptosis in BL patient-derived xenografts (BL-PDX), as well as in murine MYC-driven lymphoma allografts. This enhancement was accompanied by and required deregulation of several key genes acting in the extrinsic, death-receptor-mediated apoptotic pathway. Consistent with this mechanism of action, GSK3i also facilitated lymphoma cell killing by a death ligand TRAIL and by a death receptor agonist mapatumumab. Thus, GSK3i synergizes with both standard chemotherapeutics and direct engagers of death receptors and could improve outcomes in patients with refractory lymphomas.
Databáze: MEDLINE
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