Pharmacological targeting the ATR-CHK1-WEE1 axis involves balancing cell growth stimulation and apoptosis

Area of Science:

• Cell Biology
• Molecular Biology
• Pharmacology

Background:

• The ATR-CHK1-WEE1 kinase cascade is crucial for DNA damage checkpoints and increasingly recognized for its role in the unperturbed cell cycle.
• Small-molecule inhibitors targeting ATR, CHK1, and WEE1 are under clinical investigation, necessitating a deep understanding of cellular responses to these drugs.

Purpose of the Study:

• To investigate the effects of pharmacological inactivation of ATR, CHK1, and WEE1 on cell cycle progression and mitotic catastrophe in the absence of DNA damage.
• To explore strategies for overcoming potential limitations of single-target inhibitors within the ATR-CHK1-WEE1 axis.

Main Methods:

• Utilized small-molecule inhibitors AZD7762 (CHK1) and MK-1775 (WEE1) to inactivate specific kinases.
• Assessed mitotic catastrophe through markers like CDK1(Tyr15) dephosphorylation and histone H39(Ser10) phosphorylation.
• Evaluated cell proliferation and apoptosis rates under various inhibition conditions, including simultaneous targeting and use of kinase-inactive WEE1 variants.

Main Results:

• Pharmacological inactivation of WEE1 and CHK1, but not ATR, induced mitotic catastrophe in the absence of DNA damage.
• Partial inhibition of WEE1 and CHK1 paradoxically accelerated the cell cycle and increased proliferation, an effect also observed with kinase-inactive WEE1.
• Simultaneous inhibition of multiple components within the ATR-CHK1-WEE1 pathway effectively overcame the limitations observed with single-target inhibition.

Conclusions:

• Cellular responses to ATR-CHK1-WEE1 inhibitors are concentration-dependent and context-specific, with partial inhibition potentially promoting proliferation.
• Targeting multiple components of the ATR-CHK1-WEE1 axis simultaneously presents a promising strategy to enhance therapeutic efficacy and avoid adverse effects like accelerated cell cycling.