1. Academic Validation
  2. Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation

  • Cell Death Dis. 2021 Aug 3;12(8):763. doi: 10.1038/s41419-021-04050-7.
Viktorija Juric 1 Lance Hudson 2 Joanna Fay 3 Cathy E Richards 4 Hanne Jahns 5 Maïté Verreault 6 Franck Bielle 6 7 Ahmed Idbaih 6 7 Martine L M Lamfers 8 Ann M Hopkins 2 Markus Rehm 9 10 Brona M Murphy 11
Affiliations

Affiliations

  • 1 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.
  • 2 Department of Surgery, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, RCSI Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin, Ireland.
  • 3 Department of Pathology, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland.
  • 4 Department of Molecular Medicine, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Beaumont Hospital, Dublin, Ireland.
  • 5 Pathobiology Section, School of Veterinary Medicine, University College Dublin, Dublin, Ireland.
  • 6 INSERM U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau, Paris, France.
  • 7 AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
  • 8 Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, the Netherlands.
  • 9 Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany.
  • 10 Stuttgart Research Center Systems Biology, University of Stuttgart, Stuttgart, Germany.
  • 11 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland. [email protected].
Abstract

Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options. Since CDKs 2, 7 and 9 were found to be overexpressed in GBM, we tested the therapeutic efficacy of two CDK inhibitors (CKIs) (CYC065 and THZ1) in a heterogeneous panel of GBM patient-derived cell lines (PDCLs) cultured as gliomaspheres, as preclinically relevant models. CYC065 and THZ1 treatments suppressed invasion and induced viability loss in the majority of gliomaspheres, irrespective of the mutational background of the GBM cases, but spared primary cortical neurons. Viability loss arose from G2/M cell cycle arrest following treatment and subsequent induction of apoptotic cell death. Treatment efficacies and treatment durations required to induce cell death were associated with proliferation velocities, and Apoptosis induction correlated with complete abolishment of Mcl-1 expression, a cell cycle-regulated antiapoptotic Bcl-2 Family member. GBM models generally appeared highly dependent on Mcl-1 expression for cell survival, as demonstrated by pharmacological Mcl-1 inhibition or depletion of Mcl-1 expression. Further analyses identified CKI-induced Mcl-1 loss as a prerequisite to establish conditions at which the BH3-only protein Bim can efficiently induce Apoptosis, with cellular Bim amounts strongly correlating with treatment efficacy. CKIs reduced proliferation and promoted Apoptosis also in chick embryo xenograft models of primary and recurrent GBM. Collectively, these studies highlight the potential of these novel CKIs to suppress growth and induce cell death of patient-derived GBM cultures in vitro and in vivo, warranting further clinical investigation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-80013
    99.84%, CDK7 Inhibitor
    CDK
  • HY-101212
    99.78%, CDK2/9 Inhibitor