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. 2022 Apr;89(4):469-478.
doi: 10.1007/s00280-022-04410-w. Epub 2022 Feb 25.

Targeting Wee1 kinase to suppress proliferation and survival of cisplatin-resistant head and neck squamous cell carcinoma

Zejia Yang  1 , Jipei Liao  1 , Rena G Lapidus  1 , Xiaoxuan Fan  1 , Ranee Mehra  1 , Kevin J Cullen  2 , Hancai Dan  3   4
Affiliations

Targeting Wee1 kinase to suppress proliferation and survival of cisplatin-resistant head and neck squamous cell carcinoma

Zejia Yang et al. Cancer Chemother Pharmacol. 2022 Apr.

Abstract

Purpose: We investigated the role of Wee1 kinase in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines and determined the efficacy of either Wee1 inhibitor, AZD1775 alone, or in combination with cisplatin, on cisplatin-resistant HNSCC inhibition.

Methods: Phosphorylation and total protein levels of cells were assessed by Western blot analysis. Cell viability and apoptosis were examined by MTS assay and flow cytometry, respectively.

Results: Wee1 kinase protein expression levels in five cisplatin-resistant HNSCC cell types were higher than those in their parental cisplatin-sensitive partners. Importantly, Wee1 knockdown inhibited cell proliferation and re-sensitized cells to cisplatin treatment. Interestingly, previous studies have also shown that Wee1 inhibitor AZD1775 synergizes with cisplatin to suppress cell proliferation of cisplatin-sensitive HNSCC. We found that AZD1775 inhibited both cisplatin-sensitive and resistant HNSCC with similar IC50 values, which suggested that AZD1775 could overcome cisplatin resistance in cisplatin-resistant HNSCC. Mechanistically, AZD1775 and cisplatin cooperatively induced DNA damage and apoptosis.

Conclusion: Wee1 inhibitor, AZD1775, and cisplatin coordinately suppressed proliferation and survival of HNSCC.

Keywords: AZD1775; Cisplatin resistance; HNSCC; Head and neck squamous cell carcinoma; Wee1; Wee1 inhibitor.

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