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Mol Cancer Ther. 2019 Jun;18(6):1137-1148. doi: 10.1158/1535-7163.MCT-18-0582. Epub 2019 Mar 29.

Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer.

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Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T, Lille, France.
Univ. Lille, Plateau de génomique fonctionnelle et structurale, CHU Lille, Lille, France.
TCBN - Tumorothèque Caen Basse-Normandie, Caen, France.
Réseau Régional de Cancérologie, OncoBasseNormandie, Caen, France.
Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
Tumorothèque du C2RC de Lille, Lille, France.
Department of Digestive Surgery and Transplantation, CHU Lille, Univ Lille, Lille Cedex, France.
Department of Hepato-Gastroenterology, Rouen University Hospital, Normandie Univ, UNIROUEN, Inserm U1245, IRON group, Rouen, France.
Department of Pathology, Normandy University, INSERM 1245, Rouen University Hospital, Rouen, France.
Department of Pathology, MESOPATH-MESOBANK, Centre Léon Bérard, Lyon, France.
Thoracic Oncology Department, CIC1425/CLIP2 Paris-Nord, Hôpital Bichat-Claude Bernard, Paris, France.
Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T, Lille, France.


Besides the detection of somatic receptor tyrosine kinases (RTK) mutations in tumor samples, the current challenge is to interpret their biological relevance to give patients effective targeted treatment. By high-throughput sequencing of the 58 RTK exons of healthy tissues, colorectal tumors, and hepatic metastases from 30 patients, 38 different somatic mutations in RTKs were identified. The mutations in the kinase domains and present in both tumors and metastases were reconstituted to perform an unbiased functional study. Among eight variants found in seven RTKs (EPHA4-Met726Ile, EPHB2-Val621Ile, ERBB4-Thr731Met, FGFR4-Ala585Thr, VEGFR3-Leu1014Phe, KIT-Pro875Leu, TRKB-Leu584Val, and NTRK2-Lys618Thr), none displayed significantly increased tyrosine kinase activity. Consistently, none of them induced transformation of NIH3T3 fibroblasts. On the contrary, two RTK variants (FGFR4-Ala585Thr and FLT4-Leu1014Phe) caused drastic inhibition of their kinase activity. These findings indicate that these RTK variants are not suitable targets and highlight the importance of functional studies to validate RTK mutations as potential therapeutic targets.

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