Abstract B002: A novel NTRK2-activating internal tandem duplication characterizes a new mechanism of receptor tyrosine kinase activation
Notice bibliographique
Résumé
Abstract Personalized medicine programs, including the Zero Childhood Cancer Program (ZERO), perform molecular analysis of individual patient tumours to identify molecular targets for therapy. The comprehensive and unbiased sequencing approaches used by ZERO, including whole genome sequencing (WGS) and RNA sequencing (RNAseq), enables detection of novel structural variants (SVs) that may be cryptic to standard cytogenetic techniques or panel sequencing approaches. Identification of Receptor Tyrosine Kinase (RTK) activating variants in paediatric cancers, for example NTRK2 gene fusions, is a high priority given the availability and remarkable clinical success of RTK inhibitors. Here we describe a novel internal tandem duplication (ITD) in NTRK2, encoding TRKB, in a ZERO patient with CNS neuroblastoma. This SV was detected by WGS and was notably missed by RNAseq-based gene fusion and SV detection. The ITD spans exons 10-13 of NTRK2, is in-frame, and includes the juxtamembrane and transmembrane protein domains. We hypothesized that this ITD would result in constitutive activation of TRKB and would be sensitive to TRK-targeted therapies. We overexpressed NTRK2 ITD, wild-type NTRK2, and SPECC1L-NTRK2 (an established TRK-activating fusion), in the interleukin-3 (IL-3)-dependent cell line, Ba/F3, and the neuroblastoma cell line, SH-SY5Y. In these models, we showed that like wild-type NTRK2, NTRK2 ITD was expressed on the cell surface. NTRK2 ITD was sufficient to transform Ba/F3 cells to IL-3 independence through constitutive activation of TRKB and downstream signaling pathways PI3K/AKT and MEK/ERK. NTRK2 ITD-expressing cells were sensitive to TRK inhibitors, including larotrectinib, at similar doses to SPECC1L-NTRK2-expressing cells. Interestingly, we observed that cells expressing NTRK2 ITD were specifically sensitive to MEK inhibition, which was not observed in SPECC1L-NTRK2-expressing cells, suggesting the mechanisms by which these variants drive transformation is different. Indeed, in silico structural analysis showed that the duplicated region of NTRK2 ITD contains two internalized tyrosine residues whose phosphorylation could both drive autophosphorylation of the receptor and act as docking sites for adaptor proteins. Mutation of these tyrosine residues delayed transformation of Ba/F3 cells. This study functionally characterizes a novel NTRK2 ITD and shows that this variant is transforming and sensitive to TRK inhibition. While ITDs have been described in other RTK genes, notably FGFR1 and FLT3, structurally these have involved the kinase domain or the juxtamembrane domain. This is the first report of an ITD that spans the transmembrane domain of an RTK, characterizing an additional mechanism by which RTKs can be activated in cancer. This study highlights the value of unbiased WGS approaches to identify novel SVs and identifies another class of patients that may benefit from RTK inhibitor therapy. Citation Format: Lauren M. Brown, Gabor Tax, Pablo Acera Mateos, Antoine de Weck, Steve Foresto, Fatimah Jalud, Teresa Sadras, Pamela Ajuyah, Paulette Barahona, M. Emmy M. Dolman, Marie Wong, Chelsea Mayoh, Mark J. Cowley, Paul G. Ekert. A novel NTRK2-activating internal tandem duplication characterizes a new mechanism of receptor tyrosine kinase activation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B002.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».