Antitumor effect of WEE1 blockade as monotherapy or in combination with cisplatin in urothelial cancer.
Cancer Sci
; 112(9): 3669-3681, 2021 Sep.
Article
em En
| MEDLINE
| ID: mdl-34212455
Overcoming cisplatin (CDDP) resistance is a major issue in urothelial cancer (UC), in which CDDP-based chemotherapy is the first-line treatment. WEE1, a G2 /M checkpoint kinase, confers chemoresistance in response to genotoxic agents. However, the efficacy of WEE1 blockade in UC has not been reported. MK-1775, a WEE1 inhibitor also known as AZD-1775, blocked proliferation of UC cell lines in a dose-dependent manner irrespective of TP53 status. MK-1775 synergized with CDDP to block proliferation, inducing apoptosis and mitotic catastrophe in TP53-mutant UC cells but not in TP53-WT cells. Knocking down TP53 in TP53-WT cells induced synergism of MK-1775 and CDDP. In UMUC3 cell xenografts and two patient-derived xenograft lines with MDM2 overexpression, in which the p53/cell cycle pathway was inactivated, AZD-1775 combined with CDDP suppressed tumor growth inducing both M-phase entry and apoptosis, whereas AZD-1775 alone was as effective as the combination in RT4 cell xenografts. Drug susceptibility assay using an ex vivo cancer tissue-originated spheroid system showed correlations with the in vivo efficacy of AZD-1775 alone or combined with CDDP. We determined the feasibility of the drug susceptibility assay using spheroids established from UC surgical specimens obtained by transurethral resection. In conclusion, WEE1 is a promising therapeutic target in the treatment of UC, and a highly specific small molecule inhibitor is currently in early phase clinical trials for cancer. Differential antitumor efficacy of WEE1 blockade alone or combined with CDDP could exist according to p53/cell cycle pathway activity, which might be predictable using an ex vivo 3D primary culture system.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazóis
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Pirimidinonas
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Neoplasias da Bexiga Urinária
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Proteínas Tirosina Quinases
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Cisplatino
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Proteínas de Ciclo Celular
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Inibidores Enzimáticos
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Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Aged80
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Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article