Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib. Issue 3 (4th March 2021)

• Record Type: Journal Article
• Authors: Deland, Lily; Keane, Simon; Olsson Bontell, Thomas; Sjögren, Helene; Fagman, Henrik; Øra, Ingrid; De La Cuesta, Esther; Tisell, Magnus; Nilsson, Jonas A; Ejeskär, Katarina; Sabel, Magnus; Abel, Frida
• Is Part Of: Cancer biology & therapy. Volume 22:Issue 3(2021)
• Page Start: 184
• Page End: 195
• Publication Date: 2021-03-04
• Subjects: GKAP1 -- NTRK2 -- TRKB; fusion gene -- pLGG -- pediatric brain tumor -- precision medicine -- larotrectinib; 616.99406
• DOI: 10.1080/15384047.2021.1899573
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: Here we report a case of an 11-year-old girl with an inoperable tumor in the optic chiasm/hypothalamus, who experienced several tumor progressions despite three lines of chemotherapy treatment. Routine clinical examination classified the tumor as a BRAF -negative pilocytic astrocytoma. Copy-number variation profiling of fresh frozen tumor material identified two duplications in 9q21.32–33 leading to breakpoints within the GKAP1 and NTRK2 genes. RT-PCR Sanger sequencing revealed a GKAP1-NTRK2 exon 10–16 in-frame fusion, generating a putative fusion protein of 658 amino acids with a retained tyrosine kinase (TK) domain. Functional analysis by transient transfection of HEK293 cells showed the GKAP1-NTRK2 fusion protein to be activated through phosphorylation of the TK domain (Tyr705). Subsequently, downstream mediators of the MAPK- and PI3K-signaling pathways were upregulated in GKAP1-NTRK2 cells compared to NTRK2 wild-type; phosphorylated (p)ERK (3.6-fold), pAKT (1.8- fold), and pS6 ribosomal protein (1.4-fold). Following these findings, the patient was enrolled in a clinical trial and treated with the specific TRK-inhibitor larotrectinib, resulting in the arrest of tumor growth. The patient's condition is currently stable and the quality of life has improved significantly. Our findings highlight the value of comprehensive clinical molecular screening of BRAF -negative pediatric low-grade gliomas, to reveal rare fusions serving as targets for precision therapy.