DNA damage pathways and how CHK1-, WEE1-, or CDK1 inhibitors can synergize with cytarabine to increase its DNA damaging efficacy in AML

DNA damage pathways and how CHK1-, WEE1-, or CDK1 inhibitors can synergize with cytarabine to increase its DNA damaging efficacy in AML. Ataxia-telangectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR), radiomimetic agents, and agents which cause double-strand DNA breaks (DSBs). Ataxia-telangiectasia-related (ATR) protein kinase is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (SSB). In addition, ATM can also activate ATR. Initial sensing of DNA damage can also be mediated by the NBS1-MRE11-RAD50 complex and by RAD17-RAD1-HUS1-RAD9 at the site of DNA breaks. This is followed by phosphorylating CHK2, p53, MDM2 and CHK1, which mediate cell cycle checkpoint responses to arrest the cells until DNA damage is repaired. Activated p53 will induce p21 and the CDC25A protein, which inhibit CDK2 and prevents G1/S transition. Altered phosphorylation (by CHK1) or cytoplasmic sequestration of CDC25C (by 14-3-3σ) will inactivate CDK1/cyclin B preventing cells from entering mitosis. CHK1 also phosphorylates/activates WEE-1, which phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair. In AML, treatment with cytarabine (Ara-C) activates the DNA damage pathway through CHK1, which stabilizes stalled replication fork and induces S phase arrest. This will allow DNA damage induced by Ara-C to be repaired. To increase the DNA damaging efficacy of Ara-C the checkpoint pathway can be blocked by a selective CHK1 inhibitor such as MK-8776 that overrides the S-phase checkpoint activation. To overcome the G2/M checkpoint blocking WEE-1 kinase using the selective inhibitor MK-1775 will result in CDK1 activation and cells die due to accumulation of genetic lesions. CHEM, genotoxic chemicals; Rep stress, replication stress; UV, ultra violet radiation.

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