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

Cancer Letters
Katharina KrügerGerhard Fritz

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 medullobl...Continue Reading

Citations

Sep 29, 2019·Pharmacological Reviews·Peter J Houghton, Raushan T Kurmasheva
Jul 3, 2021·International Journal of Molecular Sciences·Laura Curti, Stefano Campaner
Sep 12, 2021·Nature Reviews. Clinical Oncology·Renumathy DhanasekaranDean W Felsher

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