Abstract B002: A novel NTRK2-activating internal tandem duplication characterizes a new mechanism of receptor tyrosine kinase activation
Bibliographic record
Abstract
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.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".