2. Academic Validation
  3. BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

  • Cancer Cell. 2019 May 13;35(5):752-766.e9. doi: 10.1016/j.ccell.2019.04.005.
Xiaohong Zhao 1,  Yuan Ren 1,  Matthew Lawlor 2,  Bijal D Shah 3,  Paul M C Park 2,  Tint Lwin 1,  Xuefeng Wang 4,  Kenian Liu 5,  Michelle Wang 1,  Jing Gao 1,  Tao Li 6,  Mousheng Xu 2,  Ariosto S Silva 7,  Kaplan Lee 8,  Tinghu Zhang 2,  John M Koomen 9,  Huijuan Jiang 10,  Praneeth R Sudalagunta 7,  Mark B Meads 1,  Fengdong Cheng 11,  Chengfeng Bi 12,  Kai Fu 12,  Huitao Fan 13,  William S Dalton 3,  Lynn C Moscinski 5,  Kenneth H Shain 3,  Eduardo M Sotomayor 11,  Gang Greg Wang 13,  Nathanael S Gray 14,  John L Cleveland 15,  Jun Qi 16,  Jianguo Tao 17
Affiliations

Affiliations

  • 1 Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3 Department of Malignant Hematology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 4 Department of Biostatistics and Bioinformatics, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 5 Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 6 Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of VIP Medical Services, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
  • 7 Department of Cancer Physiology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 8 BayCare Laboratories, LLC, Tampa, FL 33634, USA.
  • 9 Department of Molecular Oncology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 10 Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China.
  • 11 Department of Hematology and Oncology, George Washington University, Washington, DC 20052, USA.
  • 12 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68106, USA.
  • 13 Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
  • 14 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
  • 15 Department of Tumor Biology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 16 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
  • 17 Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Laboratory Medicine and Hematopathology, Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: [email protected].
PMID: 31085176 DOI: 10.1016/j.ccell.2019.04.005
Abstract

Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the Bcl-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.

Keywords

ABT-199; BCL2; CDK7; THZ1; double-hit lymphoma; drug persister; drug resistance; mantle cell lymphoma; super-enhancer remodeling; transcriptome reprogramming.

Figures
Products
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    Product Name
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  • HY-12214A
    99.20%, CDK9 Inhibitor