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Differential Sensitivity to CDK2 Inhibition Discriminates the Molecular Mechanisms of CHK1 Inhibitors as Monotherapy or in Combination with the Topoisomerase I Inhibitor SN38.

ABSTRACT: DNA damage activates checkpoints to arrest cell cycle progression in S and G2 phases, thereby providing time for repair and recovery. The combination of DNA-damaging agents and inhibitors of CHK1 (CHK1i) is an emerging strategy for sensitizing cancer cells. CHK1i induce replication on damaged DNA and mitosis before repair is complete, and this occurs in a majority of cell lines. However, ?15% of cancer cell lines are hypersensitive to single-agent CHK1i. As both abrogation of S phase arrest and single-agent activity depend on CDK2, this study resolved how activation of CDK2 can be essential for both replication and cytotoxicity. S phase arrest was induced with the topoisomerase I inhibitor SN38; the addition of CHK1i rapidly activated CDK2, inducing S phase progression that was inhibited by the CDK2 inhibitor CVT-313. In contrast, DNA damage and cytotoxicity induced by single-agent CHK1i in hypersensitive cell lines were also inhibited by CVT-313 but at 20-fold lower concentrations. The differential sensitivity to CVT-313 is explained by different activity thresholds required for phosphorylation of CDK2 substrates. While the critical CDK2 substrates are not yet defined, we conclude that hypersensitivity to single-agent CHK1i depends on phosphorylation of substrates that require high CDK2 activity levels. Surprisingly, CHK1i did not increase SN38-mediated cytotoxicity. In contrast, while inhibition of WEE1 also abrogated S phase arrest, it more directly activated CDK1, induced premature mitosis, and enhanced cytotoxicity. Hence, while high activity of CDK2 is critical for cytotoxicity of single-agent CHK1i, CDK1 is additionally required for sensitivity to the drug combination.

SUBMITTER: Warren NJH

PROVIDER: S-EPMC7088890 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Differential Sensitivity to CDK2 Inhibition Discriminates the Molecular Mechanisms of CHK1 Inhibitors as Monotherapy or in Combination with the Topoisomerase I Inhibitor SN38.

Warren Nicholas J H NJH Donahue Katelyn L KL Eastman Alan A

ACS pharmacology & translational science 20190404 3

DNA damage activates checkpoints to arrest cell cycle progression in S and G2 phases, thereby providing time for repair and recovery. The combination of DNA-damaging agents and inhibitors of CHK1 (CHK1i) is an emerging strategy for sensitizing cancer cells. CHK1i induce replication on damaged DNA and mitosis before repair is complete, and this occurs in a majority of cell lines. However, ∼15% of cancer cell lines are hypersensitive to single-agent CHK1i. As both abrogation of S phase arrest and ...[more]

PMID: 32259055

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Project description:Background: As immune checkpoint inhibitors (ICIs) transition to the forefront of cancer treatment, a better understanding of immune related adverse events (IRAEs) is essential to promote safe clinical practice. Dermatologic adverse events are the most common IRAEs and can lead to drug withdrawal and decreased quality of life. This meta-analysis aimed to investigate the risk of the most prevalent dermatologic adverse events (pruritus and rash) among various ICI treatment regimens. Methods: A systematic search of electronic databases was performed to identify qualified randomized controlled trials (RCTs). Data for any grade and high grade pruritus and rash were extracted for meta-analysis. Two reviewers independently assessed methodological quality. The relative risk summary and 95% confidence interval were calculated. Results: 50 RCTs involving 29941 patients were analyzed. The risk of pruritus (2.15 and 4.21 relative risk respectively) and rash (1.61 and 3.89 relative risk respectively) developing from CTLA-4 or PD-1/-L1 inhibitor were increased compared to placebo, but this effect was not dose-dependent. PD-1/-L1 plus CTLA-4 inhibitor was associated with increased risk of pruritus (1.76 and 0.98 relative risk respectively) and rash (1.72 and 1.37 relative risk respectively) compared to either monotherapy. Compared with CTLA-4 inhibitor, PD-1/-L1 inhibitor had a significantly decreased risk of pruritus and rash in both monotherapy and combination therapy (0.65 and 0.29 relative risk respectively). No significant difference was found between PD-1/-L1 inhibitor combined with chemotherapy and PD-1/-L1 monotherapy in any grade and high grade rash (0.84 and 1.43 relative risk respectively). In subgroup analyses, PD-1 inhibitor was associated with reduced risk of pruritus and rash compared to PD-L1 inhibitor. Conclusion: Our meta-analysis demonstrates a better safety profile for PD-1/-L1 inhibitor compared to CTLA-4 inhibitor in terms of pruritus and rash among both monotherapy and multiple combination therapies. PD-L1 inhibitor may contribute to an increased risk of pruritus and rash compared to PD-1 inhibitor.

Dataset Information

Differential Sensitivity to CDK2 Inhibition Discriminates the Molecular Mechanisms of CHK1 Inhibitors as Monotherapy or in Combination with the Topoisomerase I Inhibitor SN38.

Publications

Differential Sensitivity to CDK2 Inhibition Discriminates the Molecular Mechanisms of CHK1 Inhibitors as Monotherapy or in Combination with the Topoisomerase I Inhibitor SN38.

Similar Datasets

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