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

Deland, Lily; Keane, Simon; Bontell, Thomas Olsson; Sjögren, Helene; Fagman, Henrik; Øra, Ingrid; Cuesta, Esther De La; Tisell, Magnus; Nilsson, Jonas A.; Ejeskär, Katarina; Sabel, Magnus; Abel, Frida

doi:10.1080/15384047.2021.1899573

Cited by 9 publications

(4 citation statements)

References 61 publications

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“…ROS fusions are emerging as clinically important since they can be targeted by small inhibitors. Hence, it is becoming crucial to identify ROS-driven tumors by genetic screening so that the patients may benefit from these treatments (5,14,47,(60)(61)(62)(63). Several ROS inhibitors that have been developed are mainly tested for adult patients with NSCLC (64).…”

Section: Discussionmentioning

confidence: 99%

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

Deland

Keane

Bontell

et al. 2022

Cancer Genomics Proteomics

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Background/Aim: Although fusion genes involving the proto-oncogene receptor tyrosine kinase ROS1 are rare in pediatric glioma, targeted therapies with small inhibitors are increasingly being approved for histology-agnostic fusionpositive solid tumors. Patient and Methods: Here, we present a 16-month-old boy, with a brain tumor in the third ventricle. The patient underwent complete resection but relapsed two years after diagnosis and underwent a second operation. The tumor was initially classified as a low-grade glioma (WHO grade 2); however, methylation profiling suggested the newly WHO-recognized type: infant-type hemispheric glioma. To further refine the molecular background, and search for druggable targets, whole genome (WGS) and whole transcriptome (RNA-Seq) sequencing was performed. Results: Concomitant WGS and RNA-Seq analysis revealed several segmental gains and losses resulting in complex structural rearrangements and fusion genes. Among the top-candidates was a novel TPR::ROS1 fusion, for which only the 3' end of ROS1 was expressed in tumor tissue, indicating that wild type ROS1 is not normally expressed in the tissue of origin. Functional analysis by Western blot on protein lysates from transiently transfected HEK293 cells showed the TPR::ROS1 fusion gene to activate the MAPK-, PI3K-and JAK/STAT-pathways through increased phosphorylation of ERK, AKT, STAT and S6. The downstream pathway activation was also confirmed by immunohistochemistry on tumor tissue slides from the patient. Conclusion: We have mapped the activated oncogenic pathways of a novel ROS1-fusion gene and broadened the knowledge of the newly recognized infant-type glioma subtype. The finding facilitates suitable targeted therapies for the patient in case of relapse.The most common solid malignancies of childhood are tumors of the central nervous system (CNS). Glioma comprises the largest group of CNS tumors among these patients (40-50%), 711

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Section: Discussionmentioning

confidence: 99%

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

Deland

Keane

Bontell

et al. 2022

Cancer Genomics Proteomics

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“…Therefore, whether TrkB fusion exists in MPNSTs needs further discussion in the future. To alleviate these abnormalities, several small-molecule compounds targeting TRK fusions have been developed and tested in preclinical and clinical trials, and they have shown remarkable antitumour activities in different cancers, including different neurogenic neoplasms [ 63 , 64 ]. This study firstly suggests that further developing inhibitors targeting BDNF/TrkB signalling has great application prospects in the treatment of NF1-derived MPNSTs.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of NCOR2 Inhibits Cell Proliferation via BDNF/TrkB/ERK in NF1-Derived MPNSTs

Chung

Aimaier

et al. 2022

Cancers

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(1) Background: malignant peripheral nerve sheath tumours (MPNSTs) are aggressive Schwann cell-derived sarcomas with dismal prognoses. Previous studies have shown that nuclear receptor corepressor 2 (NCOR2) plays a vital role in neurodevelopment and in various tumours. However, the impact of NCOR2 on the progression of MPNST remains unclear. (2) Methods: by GEO database, MPNST tissue microarray, and NF1-related tumour tissues and cell lines were used to explore NCOR2 expression level in the MPNSTs. The role and mechanism of NCOR2 in NF1-derived MPNSTs were explored by experiments in vivo and in vitro and by transcriptome high-throughput sequencing. (3) Results: NCOR2 expression is significantly elevated in NF1-derived MPNSTs and is associated with patient 10-year survival time. Knockdown of NCOR2 suppressed NF1-derived MPNST cell proliferation by blocking the cell cycle in the G0/G1 phase. Moreover, decreased NCOR2 expression could down-regulate MAPK signal activity through the BDNF/TrkB pathway. (4) Conclusions: our findings demonstrated that NCOR2 expression is significantly elevated in NF1-derived MPNSTs. NCOR2 knockdown can inhibit NF1-derived MPNST cell proliferation by weakened BDNF/TrkB/ERK signalling. Targeting NF1-derived MPNSTs with TrkB inhibitors, or in combination with ERK inhibitors, may be a novel therapeutic strategy for clinical trials.

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“…The neurotrophic receptor of tyrosine kinase (NTRK) family and the ALK gene have significant roles in the development and fuctions of the CNS (81-88). In pLGGs, NTRK gene fusions including NTRK1/2/3, SLMAP-NTRK2, TPM3-NTRK1, RBPMS-NTRK3 and ETV6-NTRK3 are rare (64,76,121,122). ALK alterations are also uncommon in pLGGs, but the fusions that involved CCDC88A and PPP1CB with AKT being the more prevalent and resulting from chromothripsis (123)(124)(125).…”

Section: Other Alterations In Plggs and Targeted Therapymentioning

confidence: 99%

Unlocking the power of precision medicine for pediatric low-grade gliomas: molecular characterization for targeted therapies with enhanced safety and efficacy

et al. 2023

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In the past decade significant advancements have been made in the discovery of targetable lesions in pediatric low-grade gliomas (pLGGs). These tumors account for 30-50% of all pediatric brain tumors with generally a favorable prognosis. The latest 2021 WHO classification of pLGGs places a strong emphasis on molecular characterization for significant implications on prognosis, diagnosis, management, and the potential target treatment. With the technological advances and new applications in molecular diagnostics, the molecular characterization of pLGGs has revealed that tumors that appear similar under a microscope can have different genetic and molecular characteristics. Therefore, the new classification system divides pLGGs into several distinct subtypes based on these characteristics, enabling a more accurate strategy for diagnosis and personalized therapy based on the specific genetic and molecular abnormalities present in each tumor. This approach holds great promise for improving outcomes for patients with pLGGs, highlighting the importance of the recent breakthroughs in the discovery of targetable lesions.

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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

Cited by 9 publications

References 61 publications

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

NovelTPR::ROS1Fusion Gene Activates MAPK, PI3K and JAK/STAT Signaling in an Infant-type Pediatric Glioma

Knockdown of NCOR2 Inhibits Cell Proliferation via BDNF/TrkB/ERK in NF1-Derived MPNSTs

Unlocking the power of precision medicine for pediatric low-grade gliomas: molecular characterization for targeted therapies with enhanced safety and efficacy

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