2. Academic Validation
  3. CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma

CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma

  • Mol Cancer. 2023 Mar 30;22(1):64. doi: 10.1186/s12943-023-01762-6.
Elana Thieme # 1,  Nur Bruss # 1,  Duanchen Sun # 2 3 4,  Edward C Dominguez 1,  Daniel Coleman 2,  Tingting Liu 1,  Carly Roleder 1,  Melissa Martinez 5 6,  Krystine Garcia-Mansfield 5 6,  Brian Ball 1,  Patrick Pirrotte 5 6,  Lili Wang 1,  Zheng Xia # 2 7,  Alexey V Danilov # 8
Affiliations

Affiliations

  • 1 City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA.
  • 2 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 3 Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA.
  • 4 Present address: School of Mathematics, Shandong University, Jinan, 250100, Shandong, China.
  • 5 Translational Genomics Research Institute, Phoenix, AZ, 85004, USA.
  • 6 Integrated Mass Spectrometry Shared Resource, City of Hope National Medical Center, Duarte, CA, USA.
  • 7 Biomedical Engineering Department, Oregon Health & Science University, Portland, OR, USA.
  • 8 City of Hope National Medical Center, 1500 E Duarte Road, Duarte, CA, 91010, USA. [email protected].
  • # Contributed equally.
PMID: 36998071 DOI: 10.1186/s12943-023-01762-6
Abstract

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as Akt1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either Pim kinase or PI3K inhibitors. Both combinations decreased proliferation and induced Apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. Pim and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

Keywords

BRD4; CDK9; Mediator; PI3K; Super-enhancer.

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