2. Academic Validation
  3. Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1

Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1

  • Cancer Cell Int. 2024 Sep 13;24(1):315. doi: 10.1186/s12935-024-03489-w.
Qi Li # 1 2,  Wenjie Yang # 3,  Qingyi Zhang # 4,  Daoming Zhang # 5,  Jun Deng 6,  Binxin Chen 1 2,  Ping Li 2,  Huanqi Zhang 5,  Yiming Jiang 5,  Yangling Li 2 5,  Bo Zhang 7 8,  Nengming Lin 9 10
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 2 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, 310006, China.
  • 3 The Fourth Clinical College of Zhejiang, First People's Hospital, Chinese Medicine University, Zhejiang Chinese Medical University, Hangzhou, 310006, China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
  • 5 Research Center for Clinical Pharmacy, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 6 Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Guangxi, 530021, China.
  • 7 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China. zhangbo1009@zju.edu.cn.
  • 8 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China. zhangbo1009@zju.edu.cn.
  • 9 Department of Pharmacology, School of Basic Medical Sciences, Zhejiang University, Hangzhou, 310058, China. lnm1013@zju.edu.cn.
  • 10 Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, 310006, China. lnm1013@zju.edu.cn.
  • # Contributed equally.
PMID: 39272147 DOI: 10.1186/s12935-024-03489-w
Abstract

Background: Lung squamous cell carcinoma (LUSCs) is associated with high mortality (20-30%) and lacks of effective treatments. Almost all LUSC exhibit somatic mutations in TP53. Wee1, a tyrosine kinase, regulates the cell cycle at the G2/M checkpoint. In TP53-deficient cells, the dependence on G2/M checkpoints increases. PD0166285 is the first reported drug with inhibitory activity against both Wee1 and PKMYT1.

Methods: Protein expression was determined by Western blot analysis. Cell proliferation was assessed using cell colony formation and CCK-8 assays. Cell cycle was performed by PI staining with flow cytometry. Apoptosis was evaluated using Annexin V-Phycoerythrin double staining and flow cytometry. DNA damage was detected through comet assay and immunofluorescence assay. In vivo, Apoptosis and anti-tumor effects were assessed using the TUNEL assay, a nude mouse model, and immunohistochemistry (IHC). Co-immunoprecipitation assay was used to detect protein-protein interactions. We analyzed Wee1, PKMYT1, and STAT1 expression in pan-cancer studies using the Ualcan public database and assessed their prognostic implications with Kaplan-Meier curves.

Result: PD0166285, a Wee1 Inhibitor, effectively inhibits Wee1 activity, promoting cell entry into a mitotic crisis. Moreover, PD0166285 sensitizes cells to cisplatin, enhancing clinical outcomes. Our study demonstrated that PD016628 regulates the cell cycle through RAD51 and results in cell cycle arrest at the G2/M phase. We observed increased Apoptosis in tumor cells treated with PD0166285, particularly when combined with cisplatin, indicating an enhanced apoptotic response. The upregulation of γ-H2AX serves as an indicator of mitotic catastrophe. Co-immunoprecipitation and data analysis revealed that Apoptosis in LUSC is mediated through the STAT1 pathway, accompanied by decreased levels of Socs3. Furthermore, IHC staining confirmed significant differences in the expression of Phospho-CDK1 and γ-H2AX in LUSCs, suggesting involvement in DNA damage.

Conclusions: In summary, our study suggests that PD0166285, an inhibitor of Wee1, sensitizes LUSC cells to cisplatin and modulates DNA damage and Apoptosis pathways through RAD51 and STAT1, respectively. These findings highlight the combination of PD0166285 and cisplatin as a promising therapeutic approach for treating LUSC.

Keywords

Cell cycle; Lung squamous cell carcinoma; PD0166285; Stat1; Wee1 inhibitor.

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