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

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

I: Cancer Biology & Therapy, Vol. 22, Nr. 3, 2021, s. 184-195.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Deland, L, Keane, S, Olsson Bontell, T, Sjögren, H, Fagman, H, Øra, I, De La Cuesta, E, Tisell, M, Nilsson, JA, Ejeskär, K, Sabel, M & Abel, F 2021, 'Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib', Cancer Biology & Therapy, vol. 22, nr. 3, s. 184-195. https://doi.org/10.1080/15384047.2021.1899573

APA

Deland, L., Keane, S., Olsson Bontell, T., Sjögren, H., Fagman, H., Øra, I., De La Cuesta, E., Tisell, M., Nilsson, J. A., Ejeskär, K., Sabel, M., & Abel, F. (2021). Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib. Cancer Biology & Therapy, 22(3), 184-195. https://doi.org/10.1080/15384047.2021.1899573

CBE

Deland L, Keane S, Olsson Bontell T, Sjögren H, Fagman H, Øra I, De La Cuesta E, Tisell M, Nilsson JA, Ejeskär K, Sabel M, Abel F. 2021. Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib. Cancer Biology & Therapy. 22(3):184-195. https://doi.org/10.1080/15384047.2021.1899573

MLA

Vancouver

Author

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. / Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib. I: Cancer Biology & Therapy. 2021 ; Vol. 22, Nr. 3. s. 184-195.

RIS

TY - JOUR

T1 - Discovery of a rare GKAP1-NTRK2 fusion in a pediatric low-grade glioma, leading to targeted treatment with TRK-inhibitor larotrectinib

AU - Deland, Lily

AU - Keane, Simon

AU - Olsson Bontell, Thomas

AU - Sjögren, Helene

AU - Fagman, Henrik

AU - Øra, Ingrid

AU - De La Cuesta, Esther

AU - Tisell, Magnus

AU - Nilsson, Jonas A

AU - Ejeskär, Katarina

AU - Sabel, Magnus

AU - Abel, Frida

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1080/15384047.2021.1899573

DO - 10.1080/15384047.2021.1899573

M3 - Article

C2 - 33820494

VL - 22

SP - 184

EP - 195

JO - Cancer Biology and Therapy

JF - Cancer Biology and Therapy

SN - 1538-4047

IS - 3

ER -