Multiple DNA damage-dependent and DNA damage-independent stress responses define the outcome of ATR/Chk1 targeting in medulloblastoma cells.

Abstract

Targeting of oncogene-driven replicative stress as therapeutic option for high-risk medullobastoma was assessed using a panel of medulloblastoma cells differing in their c-Myc expression [i.e. group SHH (c-Myc low) vs. group 3 (c-Myc high)]. High c-Myc levels were associated with hypersensitivity to pharmacological Chk1 and ATR inhibition but not to CDK inhibition nor to conventional (genotoxic) anticancer therapeutics. The enhanced sensitivity of group 3 medulloblastoma cells to Chk1 inhibitors likely results from enhanced damage to intracellular organelles, elevated replicative stress and DNA damage and activation of apoptosis/necrosis. Furthermore, Chk1 inhibition differentially affected c-Myc expression and functions. In c-Myc high cells, Chk1 blockage decreased c-Myc and p-GSK3α protein and increased p21 and GADD45A mRNA expression. By contrast, c-Myc low cells revealed increased p-GSK3β protein and CHOP and DUSP1 mRNA levels. Inhibition of Chk1 sensitized medulloblastoma cells to additional replication stress evoked by cisplatin independent of c-Myc. Importantly, Chk1 inhibition only caused minor toxicity in primary rat neurons in vitro. Collectively, targeting of ATR/Chk1 effectively triggers death in high-risk medulloblastoma, potentiates the anticancer efficacy of cisplatin and is well tolerated in non-cancerous neuronal cells.

• Authors: Katharina Krüger, Katharina Geist, Fabian Stuhldreier, Lena Schumacher, Lena Blümel, Marc Remke, Sebastian Wesselborg, Björn Stork, Nicolaj Klöcker, Stefanie Bormann, Wynand P Roos, Sebastian Honnen, Gerhard Fritz
• Journal: Cancer letters (Cancer Lett) Vol. 430 Pg. 34-46 (08 28 2018) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 29753759 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Hedgehog Proteins
• MYC protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-myc
• RNA, Small Interfering
• Thiophenes
• Urea
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1
• Cisplatin

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors, metabolism)
• Caenorhabditis elegans
• Cell Line, Tumor
• Checkpoint Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Cisplatin (pharmacology, therapeutic use)
• DNA Damage (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Hedgehog Proteins (metabolism)
• Humans
• Medulloblastoma (drug therapy, genetics, pathology)
• Neurons (drug effects)
• Primary Cell Culture
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA, Small Interfering (metabolism)
• Rats
• Rats, Wistar
• Signal Transduction (drug effects, genetics)
• Thiophenes (pharmacology, therapeutic use)
• Toxicity Tests
• Urea (analogs & derivatives, pharmacology, therapeutic use)