2. Academic Validation
  3. Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma

Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma

  • Nat Commun. 2019 Jul 2;10(1):2910. doi: 10.1038/s41467-019-10993-5.
Jian-Fang Ning 1 2,  Monica Stanciu 3,  Melissa R Humphrey 4,  Joshua Gorham 5,  Hiroko Wakimoto 5,  Reiko Nishihara 6,  Jacqueline Lees 3,  Lee Zou 7 8,  Robert L Martuza 4,  Hiroaki Wakimoto 9 10,  Samuel D Rabkin 11
Affiliations

Affiliations

  • 1 Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. jning@umn.edu.
  • 2 Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, 55455, MN, USA. jning@umn.edu.
  • 3 The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA.
  • 4 Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
  • 5 Department of Genetics, Harvard Medical School, Boston, 02115, MA, USA.
  • 6 Department of Pathology, Brigham's and Women's Hospital and Harvard Medical School, Boston, 02115, MA, USA.
  • 7 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA.
  • 8 Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, 02129, MA, USA.
  • 9 Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. hwakimoto@mgh.harvard.edu.
  • 10 Brain Tumor Stem Cell Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. hwakimoto@mgh.harvard.edu.
  • 11 Molecular Neurosurgery Laboratory and the Brain Tumor Research Center and Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA. rabkin@mgh.harvard.edu.
PMID: 31266951 DOI: 10.1038/s41467-019-10993-5
Abstract

PARP inhibitors (PARPis) have clinical efficacy in BRCA-deficient cancers, but not BRCA-intact tumors, including glioblastoma (GBM). We show that MYC or MYCN amplification in patient-derived glioblastoma stem-like cells (GSCs) generates sensitivity to PARPi via Myc-mediated transcriptional repression of CDK18, while most tumors without amplification are not sensitive. In response to PARPi, CDK18 facilitates ATR activation by interacting with ATR and regulating ATR-Rad9/ATR-ETAA1 interactions; thereby promoting homologous recombination (HR) and PARPi resistance. CDK18 knockdown or ATR inhibition in GSCs suppressed HR and conferred PARPi sensitivity, with ATR inhibitors synergizing with PARPis or sensitizing GSCs. ATR Inhibitor VE822 combined with PARPi extended survival of mice bearing GSC-derived orthotopic tumors, irrespective of PARPi-sensitivity. These studies identify a role of CDK18 in ATR-regulated HR. We propose that combined blockade of ATR and PARP is an effective strategy for GBM, even for low-Myc GSCs that do not respond to PARPi alone, and potentially other PARPi-refractory tumors.

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