ArticleMolecular cancer2025
SHIP2-PLK1 crosstalk promotes sensitivity to dual inhibition in esophageal squamous cell carcinoma.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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13 authors.
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Abstract
backgroundDrug 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.
methodsTo 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.
resultsWe 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.
conclusionsOur 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.
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