Related Experiment Video
Updated: Jan 12, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
SHIP2-PLK1 crosstalk promotes sensitivity to dual inhibition in esophageal squamous cell carcinoma
Ana Raquel Ramos1, Giacomo Bregni1,2, Nadia Gillet1
1IRIBHM Jacques E. Dumont, ULB/Faculty of medicine, 808 route de Lennik, Brussels, 1070, Belgium.
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.
Insights
Combining SHIP2 and PLK1 inhibitors shows promise for treating esophageal squamous cell carcinoma (eSCC). This synergistic approach may overcome drug resistance and improve patient outcomes in eSCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Drug synergy enhances cancer therapy efficacy and reduces side effects.
- Esophageal squamous cell carcinoma (eSCC) has a poor prognosis and limited treatment options.
- Targeted therapies are often inefficient in eSCC due to resistance.
Purpose of the Study:
- Investigate novel therapeutic strategies for eSCC.
- Identify key molecular targets and pathways involved in eSCC progression.
- Explore the potential of drug combinations to overcome eSCC resistance.
Main Methods:
- Utilized human eSCC cell lines and xenotransplant models.
- Employed CRISPR/Cas9 genetic manipulation and RNA sequencing.
- Assessed the role of SHIP2 in eSCC cell behavior and signaling pathways.
Main Results:
- SHIP2, encoded by INPPL1, is prevalent in eSCC and affects cell survival, proliferation, and adhesion.
- SHIP2 inhibition decreases AKT phosphorylation and perturbs cell cycle transcripts.
- PLK1 was identified as a downregulated transcript upon SHIP2 inhibition, suggesting synergistic potential.
Conclusions:
- SHIP2 inhibitors combined with PLK1 inhibitors offer a promising strategy for eSCC treatment.
- This combination can stall eSCC growth, enhance treatment response, and circumvent resistance.
- The study elucidates SHIP2's role in the PI3K/AKT pathway and cell cycle in eSCC, guiding targeted interventions.
