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Background <p>Drug synergy in cancer therapy has gained attention for its potential to enhance efficacy and minimize adverse effects. Synergy, where the combined effect of drugs exceeds the sum of their individual effects, is beneficial in addressing tumor heterogeneity and drug resistance in oncology. Esophageal squamous cell carcinoma (eSCC), accounting for over 85% of esophageal cancer cases, has a poor prognosis and limited therapeutic options. Targeted therapies have shown inefficiency in eSCC due to resistance mechanisms, making drug combination an interesting option.</p> Methods <p>To investigate new therapeutic startegies in eSCC, we utilized a combination of multiple human eSCC cell lines, xenotransplant models, primary mouse eSCC model, CRISPR/Cas9-based genetic manipulation and RNA sequencing analysis.</p> Results <p>We report the role of SHIP2, a phosphoinositide (PI) 5-phosphatase, in eSCC. Amplification of the <i>INPPL1</i> gene, encoding SHIP2, was prevalent in eSCC, linked to elevated SHIP2 transcript levels. SHIP2 knockdown and pharmacological inhibition demonstrated its influence on eSCC cell survival, proliferation, and adhesion, partially by decreasing AKT phosphorylation and perturbing cell cycle-associated transcripts. SHIP2’s impact was not restricted to cells harboring <i>INPPL1</i> amplification, implying its potential activity across diverse eSCC subtypes. Compensation mechanisms emerged in SHIP2-deficient eSCC cells, highlighting the necessity of combinatory approaches to counteract resistance. RNA sequencing identified PLK1 as a prominent downregulated transcript upon SHIP2 inhibition, revealing synergistic potential with PLK1 inhibitors.</p> Conclusions <p>Our data support the use of specific SHIP2 inhibitors, in combination with PLK1 inhibitors, as a promising strategy for stalling eSCC growth, amplifying treatment response, and circumventing resistance. This study unravels the intricate interplay of SHIP2 within the PI3K/AKT pathway and cell cycle in eSCC, paving the way for targeted interventions with the potential to transform the therapeutic landscape of this challenging malignancy.</p>

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SHIP2–PLK1 crosstalk promotes sensitivity to dual inhibition in esophageal squamous cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月4日

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  • Ana Raquel Ramos,
  • Giacomo Bregni,
  • Nadia Gillet,
  • Kunie Ando,
  • Cyril Bodart,
  • Alizée Vercauteren Drubbel,
  • Louison Descampe,
  • Fabiana Moresi,
  • Xavier Bisteau,
  • Quentin Verheye,
  • Sheleya Pirard,
  • Christophe Erneux,
  • Benjamin Beck

摘要

Background

Drug synergy in cancer therapy has gained attention for its potential to enhance efficacy and minimize adverse effects. Synergy, where the combined effect of drugs exceeds the sum of their individual effects, is beneficial in addressing tumor heterogeneity and drug resistance in oncology. Esophageal squamous cell carcinoma (eSCC), accounting for over 85% of esophageal cancer cases, has a poor prognosis and limited therapeutic options. Targeted therapies have shown inefficiency in eSCC due to resistance mechanisms, making drug combination an interesting option.

Methods

To investigate new therapeutic startegies in eSCC, we utilized a combination of multiple human eSCC cell lines, xenotransplant models, primary mouse eSCC model, CRISPR/Cas9-based genetic manipulation and RNA sequencing analysis.

Results

We report the role of SHIP2, a phosphoinositide (PI) 5-phosphatase, in eSCC. Amplification of the INPPL1 gene, encoding SHIP2, was prevalent in eSCC, linked to elevated SHIP2 transcript levels. SHIP2 knockdown and pharmacological inhibition demonstrated its influence on eSCC cell survival, proliferation, and adhesion, partially by decreasing AKT phosphorylation and perturbing cell cycle-associated transcripts. SHIP2’s impact was not restricted to cells harboring INPPL1 amplification, implying its potential activity across diverse eSCC subtypes. Compensation mechanisms emerged in SHIP2-deficient eSCC cells, highlighting the necessity of combinatory approaches to counteract resistance. RNA sequencing identified PLK1 as a prominent downregulated transcript upon SHIP2 inhibition, revealing synergistic potential with PLK1 inhibitors.

Conclusions

Our data support the use of specific SHIP2 inhibitors, in combination with PLK1 inhibitors, as a promising strategy for stalling eSCC growth, amplifying treatment response, and circumventing resistance. This study unravels the intricate interplay of SHIP2 within the PI3K/AKT pathway and cell cycle in eSCC, paving the way for targeted interventions with the potential to transform the therapeutic landscape of this challenging malignancy.