Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations
Wee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1,...
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| Format: | Article |
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MDPI AG
2019-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/6/819 |
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| author | Angela Flavia Serpico Giuseppe D’Alterio Cinzia Vetrei Rosa Della Monica Luca Nardella Roberta Visconti Domenico Grieco |
| author_facet | Angela Flavia Serpico Giuseppe D’Alterio Cinzia Vetrei Rosa Della Monica Luca Nardella Roberta Visconti Domenico Grieco |
| author_sort | Angela Flavia Serpico |
| collection | DOAJ |
| description | Wee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1, alone or in combination with DNA damaging agents, can kill cancer cells by mitotic catastrophe, a tumor suppressive response that follows mitosis onset in the presence of under-replicated or damaged DNA. AZD1775, an orally available Wee1 inhibitor, has entered clinical trials for cancer treatment following this strategy, with promising results. Recently, however, AZD1775 has been shown to inhibit also the polo-like kinase homolog Plk1 in vitro, casting doubts on its mechanism of action. Here we asked whether, in the clinically relevant concentration range, AZD1775 inhibited Wee1 or Plk1 in transformed and non-transformed human cells. We found that in the clinically relevant, nanomolar, concentration range AZD1775 inhibited Wee1 rather than Plk1. In addition, AZD1775 treatment accelerated mitosis onset overriding the DNA replication checkpoint and hastened Plk1-dependent phosphorylation. On the contrary selective Plk1 inhibition exerted opposite effects. Thus, at therapeutic concentrations, AZD1775 inhibited Wee1 rather than Plk1. This information will help to better interpret results obtained by using AZD1775 both in the clinical and experimental settings and provide a stronger rationale for combination therapies. |
| first_indexed | 2024-03-12T05:56:45Z |
| format | Article |
| id | doaj.art-ad97dc6825f941a3ab65d240635976e3 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T05:56:45Z |
| publishDate | 2019-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-ad97dc6825f941a3ab65d240635976e32023-09-03T04:30:08ZengMDPI AGCancers2072-66942019-06-0111681910.3390/cancers11060819cancers11060819Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant ConcentrationsAngela Flavia Serpico0Giuseppe D’Alterio1Cinzia Vetrei2Rosa Della Monica3Luca Nardella4Roberta Visconti5Domenico Grieco6CEINGE Biotecnologie Avanzate, 80145 Naples, ItalyCEINGE Biotecnologie Avanzate, 80145 Naples, ItalyCEINGE Biotecnologie Avanzate, 80145 Naples, ItalyCEINGE Biotecnologie Avanzate, 80145 Naples, ItalyCEINGE Biotecnologie Avanzate, 80145 Naples, ItalyIEOS, CNR, 80131 Naples, ItalyCEINGE Biotecnologie Avanzate, 80145 Naples, ItalyWee1 kinase is an inhibitor of cyclin-dependent kinase (cdk)s, crucial cell cycle progression drivers. By phosphorylating cdk1 at tyrosine 15, Wee1 inhibits activation of cyclin B-cdk1 (Cdk1), preventing cells from entering mitosis with incompletely replicated or damaged DNA. Thus, inhibiting Wee1, alone or in combination with DNA damaging agents, can kill cancer cells by mitotic catastrophe, a tumor suppressive response that follows mitosis onset in the presence of under-replicated or damaged DNA. AZD1775, an orally available Wee1 inhibitor, has entered clinical trials for cancer treatment following this strategy, with promising results. Recently, however, AZD1775 has been shown to inhibit also the polo-like kinase homolog Plk1 in vitro, casting doubts on its mechanism of action. Here we asked whether, in the clinically relevant concentration range, AZD1775 inhibited Wee1 or Plk1 in transformed and non-transformed human cells. We found that in the clinically relevant, nanomolar, concentration range AZD1775 inhibited Wee1 rather than Plk1. In addition, AZD1775 treatment accelerated mitosis onset overriding the DNA replication checkpoint and hastened Plk1-dependent phosphorylation. On the contrary selective Plk1 inhibition exerted opposite effects. Thus, at therapeutic concentrations, AZD1775 inhibited Wee1 rather than Plk1. This information will help to better interpret results obtained by using AZD1775 both in the clinical and experimental settings and provide a stronger rationale for combination therapies.https://www.mdpi.com/2072-6694/11/6/819Wee1 inhibitorPlk1 inhibitorDNA replication checkpointcombination therapyconcentration range |
| spellingShingle | Angela Flavia Serpico Giuseppe D’Alterio Cinzia Vetrei Rosa Della Monica Luca Nardella Roberta Visconti Domenico Grieco Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations Cancers Wee1 inhibitor Plk1 inhibitor DNA replication checkpoint combination therapy concentration range |
| title | Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations |
| title_full | Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations |
| title_fullStr | Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations |
| title_full_unstemmed | Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations |
| title_short | Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations |
| title_sort | wee1 rather than plk1 is inhibited by azd1775 at therapeutically relevant concentrations |
| topic | Wee1 inhibitor Plk1 inhibitor DNA replication checkpoint combination therapy concentration range |
| url | https://www.mdpi.com/2072-6694/11/6/819 |
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