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

Abstract

// Raquel Carvalho Montenegro 1 , Alison Howarth 2 , Alessandro Ceroni 2 , Vita Fedele 2 , Batoul Farran 3 , Felipe Pantoja Mesquita 1 , Martin Frejno 4 , Benedict-Tilman Berger 5 , 6 , Stephanie Heinzlmeir 4 , 7 , Heba Z. Sailem 8 , 9 , Roberta Tesch 5 , 6 , Daniel Ebner 2 , Stefan Knapp 5 , 6 , Rommel Burbano 10 , Bernhard Kuster 4 , 7 , 11 and Susanne Müller 5 1 Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil 2 Novo Nordisk Research Centre Oxford (NNRCO), Discovery Technologies and Genomics, Oxford, UK 3 Winship Cancer Institute, Emory University, Atlanta, GA, USA 4 Chair of Proteomics and Bioanalytics, Technical University of Munich, Freising, Germany 5 Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Frankfurt, Germany 6 Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Frankfurt, Germany 7 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Institute of Biomedical Engineering, Department of Engineering, University of Oxford, Oxford, UK 9 Big Data Institute, University of Oxford, Li Ka Shing Centre for Health Information and Discovery, Old Road Campus Research Building, Oxford, UK 10 Ophir Loyola Hospital, Belém, PA, Brazil 11 Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technische Universität München, Freising, Germany Correspondence to: Raquel Carvalho Montenegro, email: [email protected] Susanne Müller, email: [email protected] Keywords: gastric cancer; dasatinib; biomarker; SRC-kinases; SIK2 Received: November 16, 2019     Accepted: January 13, 2020     Published: February 04, 2020 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.

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