Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Lily Deland
  • Simon Keane
  • Thomas Olsson Bontell
  • Helene Sjögren
  • Henrik Fagman
  • Ingrid Øra
  • Esther De La Cuesta
  • Magnus Tisell
  • Jonas A Nilsson
  • Katarina Ejeskär
  • Magnus Sabel
  • Frida Abel
Enheter & grupper
Externa organisationer
  • University of Skövde
  • Göteborgs universitet
  • Sahlgrenska University Hospital
  • Karolinska University Hospital
  • Bayer Corporation, USA
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)184-195
TidskriftCancer Biology & Therapy
Volym22
Utgåva nummer3
Tidigt onlinedatum2021 apr 5
StatusPublished - 2021
PublikationskategoriForskning
Peer review utfördJa