Identification of molecular targets for the targeted treatment of gastric cancer using dasatinib

Raquel Carvalho Montenegro, Alison Howarth, Alessandro Ceroni, Vita Fedele, Batoul Farran, Felipe Pantoja Mesquita, Martin Frejno, Benedict Tilman Berger, Stephanie Heinzlmeir, Heba Z. Sailem, Roberta Tesch, Daniel Ebner, Stefan Knapp, Rommel Burbano, Bernhard Kuster, Susanne Müller

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)535-549
Number of pages15
JournalOncotarget
Volume11
Issue number5
StatePublished - Feb 1 2020
Externally publishedYes

Keywords

  • Biomarker
  • Dasatinib
  • Gastric cancer
  • SIK2
  • SRC-kinases

ASJC Scopus subject areas

  • Oncology

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