Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib
Raquel Carvalho Montenegro1, Alison Howarth2, Alessandro Ceroni2
1Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil.
Abstract:
Gastric cancer (GC) remains the third leading cause of cancer-related death despite several improvements in targeted therapy. There is therefore an urgent need to investigate new treatment strategies, including the identification of novel biomarkers for patient stratification. In this study, we evaluated the effect of FDA-approved kinase inhibitors on GC. Through a combination of cell growth, migration and invasion assays, we identified dasatinib as an efficient inhibitor of GC proliferation. Mass-spectrometry-based selectivity profiling and subsequent knockdown experiments identified members of the SRC family of kinases including SRC, FRK, LYN and YES, as well as other kinases such as DDR1, ABL2, SIK2, RIPK2, EPHA2, and EPHB2 as dasatinib targets. The expression levels of the identified kinases were investigated on RNA and protein level in 200 classified tumor samples from patients, who had undergone gastrectomy, but had received no treatment. Levels of FRK, DDR1 and SRC expression on both mRNA and protein level were significantly higher in metastatic patient samples regardless of the tumor stage, while expression levels of SIK2 correlated with tumor size. Collectively, our data suggest dasatinib for treatment of GC based on its unique property, inhibiting a small number of key kinases (SRC, FRK, DDR1 and SIK2), highly expressed in GC patients.
Insights
Dasatinib effectively inhibits gastric cancer (GC) proliferation by targeting key kinases like SRC, FRK, and DDR1. These kinases are highly expressed in GC patients, suggesting dasatinib as a potential targeted therapy for gastric cancer.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Gastric cancer (GC) is a leading cause of cancer death, necessitating novel targeted therapies and biomarkers.
- Current targeted therapies for GC show limitations, highlighting the need for new treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of FDA-approved kinase inhibitors as potential treatments for gastric cancer.
- To identify novel biomarkers for patient stratification in gastric cancer therapy.
Main Methods:
- In vitro assays (cell growth, migration, invasion) to assess dasatinib's effect on GC.
- Mass spectrometry for kinase inhibitor profiling and knockdown experiments to identify dasatinib targets.
- Analysis of kinase expression (mRNA and protein) in 200 patient tumor samples.
Main Results:
- Dasatinib demonstrated significant inhibition of gastric cancer proliferation.
- Key dasatinib targets identified include SRC family kinases (SRC, FRK, LYN, YES) and others (DDR1, ABL2, SIK2, RIPK2, EPHA2, EPHB2).
- Elevated FRK, DDR1, and SRC expression correlated with metastasis; SIK2 expression correlated with tumor size in GC patients.
Conclusions:
- Dasatinib shows promise as a gastric cancer treatment due to its inhibition of highly expressed kinases (SRC, FRK, DDR1, SIK2).
- FRK, DDR1, SRC, and SIK2 represent potential biomarkers for patient stratification and targeted therapy in gastric cancer.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:34Inhibition of Cdk Activity