2. Academic Validation
  3. Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

Combination therapy with WEE1 inhibition and trifluridine/tipiracil against esophageal squamous cell carcinoma

  • Cancer Sci. 2023 Sep 19. doi: 10.1111/cas.15966.
Trang H Nguyen Vu 1 2,  Osamu Kikuchi 3 4,  Shinya Ohashi 1 5,  Tomoki Saito 1,  Tomomi Ida 1,  Yukie Nakai 1,  Yang Cao 1,  Yoshihiro Yamamoto 1,  Yuki Kondo 1,  Yosuke Mitani 1,  Shigeki Kataoka 1,  Tomohiro Kondo 1,  Chikatoshi Katada 1,  Atsushi Yamada 1,  Junichi Matsubara 1,  Manabu Muto 1 3
Affiliations

Affiliations

  • 1 Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  • 2 Endoscopy Department, Cho Ray Hospital, Ho Chi Minh City, Vietnam.
  • 3 Department of Clinical Bio-Resource Center, Kyoto University Hospital, Kyoto, Japan.
  • 4 Division of Clinical Pharmacology and Cancer Immunotherapy, Kyoto University Center for Cancer Immunotherapy and Immunobiology, Kyoto, Japan.
  • 5 Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital, Kyoto, Japan.
PMID: 37724648 DOI: 10.1111/cas.15966
Abstract

Despite advanced therapeutics, esophageal squamous cell carcinoma (ESCC) remains one of the deadliest cancers. Here, we propose a novel therapeutic strategy based on synthetic lethality combining trifluridine/tipiracil and MK1775 (Wee1 Inhibitor) as a treatment for ESCC. This study demonstrates that trifluridine induces single-strand DNA damage in ESCC cells, as evidenced by phosphorylated replication protein 32. The DNA damage response includes cyclin-dependent kinase 1 (CDK1) (Tyr15) phosphorylation as CDK1 inhibition and a decrease of the proportion of phospho-histone H3 (p-hH3)-positive cells, indicating cell cycle arrest at the G2 phase before mitosis entry. The Wee1 Inhibitor remarkedly suppressed CDK1 phosphorylation (Try15) and reactivated CDK1, and also increased the proportion of p-hH3-positive cells, which indicates an increase of the number of cells into mitosis. Trifluridine combined with a Wee1 Inhibitor increased trifluridine-mediated DNA damage, namely DNA double-strand breaks, as shown by increased γ-H2AX expression. Moreover, the combination treatment with trifluridine/tipiracil and a Wee1 Inhibitor significantly suppressed tumor growth of ESCC-derived xenograft models. Hence, our novel combination treatment with trifluridine/tipiracil and a Wee1 Inhibitor is considered a candidate treatment strategy for ESCC.

Keywords

DNA damage response; WEE1 inhibitor; esophageal squamous cell carcinoma; synthetic lethality; trifluridine.

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