Skip to Main content Skip to Navigation
Journal articles

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

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
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 : Wednesday, August 19, 2020 - 11:18:49 AM

Links full text

Identifiers

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⟩

Share

Metrics

Record views

65