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Journal articles
Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer
Leslie Duplaquet
1
Martin Figeac
2
Frederic Lepretre
2
Charline Frandemiche
3
Céline Villenet
2
Shéhérazade Sebda
2
Nasrin Sarafan-Vasseur
4
Mélanie Bénozène
1
Audrey Vinchent
1
Gautier Goormachtigh
1
Laurence Wicquart
5, 6
Nathalie Rousseau
3
Ludivine Beaussire
4
Stéphanie Truant
7
Pierre Michel
4
Jean-Christophe Sabourin
4
Françoise Galateau-Salle
8
Marie-Christine Copin
1
Gérard Zalcman
9
Yvan de Launoit
1
Véronique Fafeur
1
David Tulasne
1, *
*
Corresponding author
Leslie Duplaquet 1
Author
Martin Figeac 2
Author
Frederic Lepretre 2
Author
Charline Frandemiche 3
Author
Céline Villenet 2
Author
Shéhérazade Sebda 2
Author Employer institution : Institut de Recherche sur le Cancer de Lille
Nasrin Sarafan-Vasseur 4
Author IdHAL : nasrin-vasseur
Mélanie Bénozène 1
Author
Audrey Vinchent 1
Author
Gautier Goormachtigh 1
Author IdHAL : gautier-goormachtigh ORCID : https://orcid.org/0000-0003-1736-8269
Laurence Wicquart 5, 6
Author
Nathalie Rousseau 3
Author
Ludivine Beaussire 4
Author
Stéphanie Truant 7
Author
Pierre Michel 4
Author
Jean-Christophe Sabourin 4
Author
Françoise Galateau-Salle 8
Author
Marie-Christine Copin 1
Author
Gérard Zalcman 9
Author
Yvan de Launoit 1
Author
Véronique Fafeur 1
Author
David Tulasne 1
Correspondent author
1
M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées (M3T) - UMR 8161 (France)
- INSERM - Institut National de la Santé et de la Recherche Médicale (101, rue de Tolbiac, 75013 Paris - France)
- Université de Lille (Lille - France)
- Institut Pasteur de Lille (1 Rue du Professeur Calmette - Lille Cedex - 59019 - France)
- RIIP - Réseau International des Instituts Pasteur (25, rue du Dr Roux 75724 Paris Cedex 15 - France)
- CNRS - Centre National de la Recherche Scientifique : 8161 (France)
2
Plateforme de génomique fonctionnelle et structurelle [Lille] (France)
- IRCL - Institut pour la recherche sur le cancer de Lille [Lille] (France)
- Université de Lille, Droit et Santé (42 rue Paul Duez 59000 Lille - France)
3
TCBN - Tumorothèque de Caen Basse-Normandie (3 avenue du Général Harris
14076 Caen cedex 5 - France)
4
GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (22, Boulevard Gambetta 76183 Rouen Cedex - France)
- UNIROUEN - Université de Rouen Normandie (1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex - France)
- NU - Normandie Université (Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U1245 (101, rue de Tolbiac, 75013 Paris - France)
5
Institut de Pathologie et Tumorothèque du C2RC (France)
- CHRU Lille - Centre Hospitalier Régional Universitaire [Lille] (2, avenue Oscar Lambret - 59037 Lille Cedex - France)
6
GCS-C2RC - Registre général des cancers de Lille et de sa région (Pavillon Breton - Boulevard du Professeur Jules Leclercq 59037 Lille Cedex - France)
- CHRU Lille - Centre Hospitalier Régional Universitaire [Lille] (2, avenue Oscar Lambret - 59037 Lille Cedex - France)
- Hôpital Albert Calmette [Lille] (Bd du Professeur jules Leclercq, 59000 Lille - France)
7
CHRU Lille - Centre Hospitalier Régional Universitaire [Lille] (2, avenue Oscar Lambret - 59037 Lille Cedex - France)
8
MESOPATH Referent National Center (France)
- Centre Léon Bérard [Lyon] (28, rue Laennec 69373 LYON Cedex 08 - France)
9
Service d’oncologie thoracique et essais précoces [CHU Bichat] (France)
- AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) (France)
- AP-HP - Hôpital Bichat - Claude Bernard [Paris] (46 Rue Henri Huchard, 75018 Paris - France)
Abstract : 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.
Document type :
Journal articles
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Complete list of metadatas
https://hal-normandie-univ.archives-ouvertes.fr/hal-02352974
Contributor : Nasrin Vasseur <>
Submitted on : Thursday, November 7, 2019 - 10:14:25 AM
Last modification on : Friday, January 8, 2021 - 3:34:02 PM
Contributor : Nasrin Vasseur <>
Submitted on : Thursday, November 7, 2019 - 10:14:25 AM
Last modification on : Friday, January 8, 2021 - 3:34:02 PM
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Identifiers
- HAL Id : hal-02352974, version 1
- PUBMED : 30926633
- DOI : 10.1158/1535-7163.MCT-18-0582
Collections
COMUE-NORMANDIE | RIIP | RIIP_LILLE | CNRS | UNIROUEN | UNIV-LILLE | GPMCND
Citation
Leslie Duplaquet, Martin Figeac, Frederic Lepretre, Charline Frandemiche, Céline Villenet, et al.. Functional Analysis of Somatic Mutations Affecting Receptor Tyrosine Kinase Family in Metastatic Colorectal Cancer. Molecular Cancer Therapeutics, American Association for Cancer Research, 2019, 18 (6), pp.1137-1148. ⟨10.1158/1535-7163.MCT-18-0582⟩. ⟨hal-02352974⟩
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