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Serpico AF, D'Alterio G, Vetrei C, et al. Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations. Cancers (Basel). 2019;11(6)doi: 10.3390/cancers11060819.
Serpico, A. F., D'Alterio, G., Vetrei, C., Della Monica, R., Nardella, L., Visconti, R., & Grieco, D. (2019). Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations. Cancers, 11(6), . https://doi.org/10.3390/cancers11060819
Serpico, Angela Flavia, et al. "Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations." Cancers vol. 11,6 (2019). doi: https://doi.org/10.3390/cancers11060819
Serpico AF, D'Alterio G, Vetrei C, Della Monica R, Nardella L, Visconti R, Grieco D. Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations. Cancers (Basel). 2019 Jun 13;11(6). doi: 10.3390/cancers11060819. PMID: 31200459; PMCID: PMC6627824.
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Cancers (Basel). 2019 Jun 13;11(6). doi: 10.3390/cancers11060819.

Wee1 Rather Than Plk1 Is Inhibited by AZD1775 at Therapeutically Relevant Concentrations.

Cancers

Angela Flavia Serpico, Giuseppe D'Alterio, Cinzia Vetrei, Rosa Della Monica, Luca Nardella, Roberta Visconti, Domenico Grieco

Affiliations

  1. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy. [email protected].
  2. DMMBM, University of Naples "Federico II", 80131 Naples, Italy. [email protected].
  3. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy. [email protected].
  4. DMMBM, University of Naples "Federico II", 80131 Naples, Italy. [email protected].
  5. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy. [email protected].
  6. DMMBM, University of Naples "Federico II", 80131 Naples, Italy. [email protected].
  7. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy. [email protected].
  8. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy. [email protected].
  9. DMMBM, University of Naples "Federico II", 80131 Naples, Italy. [email protected].
  10. IEOS, CNR, 80131 Naples, Italy. [email protected].
  11. CEINGE Biotecnologie Avanzate, 80145 Naples, Italy. [email protected].
  12. Department of Pharmacy, University of Naples "Federico II", 80131 Naples, Italy. [email protected].

PMID: 31200459 PMCID: PMC6627824 DOI: 10.3390/cancers11060819

Abstract

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.

Keywords: DNA replication checkpoint; Plk1 inhibitor; Wee1 inhibitor; combination therapy; concentration range

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