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. Author manuscript; available in PMC: 2015 Jan 28.
Published in final edited form as: Cancer Lett. 2014 Oct 18;356(2 0 0):656–668. doi: 10.1016/j.canlet.2014.10.015

Fig. 8.

Fig. 8

Proposed mechanism for the antitumor interactions between MK-1775 and panobinostat in pancreatic cancer. Inhibition of Wee1 reduces phosphorylation of CDK1/CDK2, allowing CDK1/CDK2 to remain active, which leads to DNA damage. DNA damage triggers activation of ATM/ATR, which then activates CHK1. Active CHK1 inhibits CDC25s, leading to decreased removal of the inhibitory phosphorylation on CDK1/CDK2, resulting in increased p-CDK1/p-CDK2. This limits the amount of active CDK1/CDK2 and the resulting DNA damage following MK-1775 treatment. Panobinostat inhibits activation of CHK1, thus maintaining the active CDK1/CDK2 pools, enhancing DNA damage, and eventually leading to apoptosis. Others have suggested that CHK1 can activate Wee1, as indicated by the dashed line.