2. Academic Validation
  3. Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma

Transcriptional programming drives Ibrutinib-resistance evolution in mantle cell lymphoma

  • Cell Rep. 2021 Mar 16;34(11):108870. doi: 10.1016/j.celrep.2021.108870.
Xiaohong Zhao 1,  Michelle Y Wang 1,  Huijuan Jiang 1,  Tint Lwin 1,  Paul M Park 2,  Jing Gao 1,  Mark B Meads 3,  Yuan Ren 1,  Tao Li 1,  Jiao Sun 4,  Naima Ahmed Fahmi 4,  Satishkumar Singh 5,  Lalit Sehgal 5,  Xuefeng Wang 6,  Ariosto S Silva 7,  Eduardo M Sotomayor 8,  Kenneth H Shain 3,  John L Cleveland 9,  Michael Wang 10,  Wei Zhang 4,  Jun Qi 2,  Bijal D Shah 11,  Jianguo Tao 12
Affiliations

Affiliations

  • 1 Chemical Biology and Molecular Medicine Program, H. Lee 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, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 4 Department of Computer Science, University of Central Florida, Orlando, FL 32816, USA.
  • 5 Department of Internal Medicine, The Ohio State University, Columbus, OH 32816, USA.
  • 6 Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 7 Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 8 Department of Hematology and Oncology, George Washington University, Washington, D.C. 20052, USA.
  • 9 Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
  • 10 Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 11 Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: bijal.shah@moffitt.org.
  • 12 Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA. Electronic address: jianguo.tao@moffitt.org.
PMID: 33730585 DOI: 10.1016/j.celrep.2021.108870
Abstract

Ibrutinib, a bruton's tyrosine kinase (Btk) inhibitor, provokes robust clinical responses in aggressive mantle cell lymphoma (MCL), yet many patients relapse with lethal Ibrutinib-resistant (IR) disease. Here, using genomic, chemical proteomic, and drug screen profiling, we report that enhancer remodeling-mediated transcriptional activation and adaptive signaling changes drive the aggressive phenotypes of IR. Accordingly, IR MCL cells are vulnerable to inhibitors of the transcriptional machinery and especially so to inhibitors of cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Further, CDK9 inhibition disables reprogrammed signaling circuits and prevents the emergence of IR in MCL. Finally, and importantly, we find that a robust and facile ex vivo image-based functional drug screening platform can predict clinical therapeutic responses of IR MCL and identify vulnerabilities that can be targeted to disable the evolution of IR.

Keywords

BRD4; CDK9; Ibrutinib; combination therapy; enhancer; kinome; mantle cell lymphoma; resistance; transcriptome.

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