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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
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Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

Trang H Nguyen Vu1,2, Osamu Kikuchi3,4, Shinya Ohashi1,5

  • 1Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Cancer Science
|September 19, 2023
PubMed

Insights

This study explores a new esophageal squamous cell carcinoma (ESCC) treatment combining trifluridine/tipiracil and a WEE1 inhibitor. This synthetic lethality approach shows promise in suppressing ESCC tumor growth.

Area of Science:

  • Oncology
  • Cancer Therapeutics
  • Molecular Biology

Background:

  • Esophageal squamous cell carcinoma (ESCC) presents a significant challenge despite current treatments.
  • Synthetic lethality offers a promising avenue for novel cancer therapies.

Purpose of the Study:

  • To investigate the efficacy of combining trifluridine/tipiracil with a WEE1 inhibitor (MK1775) as a novel therapeutic strategy for ESCC.
  • To elucidate the molecular mechanisms underlying this combination therapy's action on ESCC cells.

Main Methods:

  • Assessing trifluridine-induced DNA damage via phosphorylated replication protein 32.
  • Analyzing cell cycle progression, including cyclin-dependent kinase 1 (CDK1) phosphorylation and phospho-histone H3 (p-hH3) expression.
  • Evaluating the impact of WEE1 inhibition on cell cycle regulation and DNA damage.
  • Testing the combination therapy in ESCC-derived xenograft models.

Main Results:

  • Trifluridine induced single-strand DNA damage and G2 cell cycle arrest.
  • WEE1 inhibition reactivated CDK1 and promoted mitotic entry.
  • The combination therapy enhanced trifluridine-induced DNA damage, leading to double-strand breaks (γ-H2AX expression).
  • Combined treatment significantly suppressed tumor growth in ESCC xenograft models.

Conclusions:

  • The combination of trifluridine/tipiracil and a WEE1 inhibitor represents a novel synthetic lethality approach for ESCC.
  • This strategy effectively targets ESCC by inducing DNA damage and disrupting cell cycle regulation.
  • The combination therapy demonstrates significant potential as a candidate treatment for esophageal squamous cell carcinoma.
Keywords:
DNA damage responseWEE1 inhibitoresophageal squamous cell carcinomasynthetic lethalitytrifluridine

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