Mechanisms of targeted therapy resistance in a pediatric glioma driven by ETV6-NTRK3 fusion
- Clare Keddy1,
- Tanaya Neff2,
- Jianya Huan3,
- Joshua P. Nickerson4,
- Catherine Z. Beach1,
- Yassmine Akkari5,
- Jianling Ji6,
- Stephen Moore7,
- Kellie J. Nazemi1,
- Christopher L. Corless2,3,
- Carol Beadling2,
- Randy Woltjer3,
- Yoon-Jae Cho1,
- Matthew D. Wood2,3 and
- Monika A. Davare1
- 1Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97239, USA;
- 2Knight Diagnostic Laboratories, Oregon Health & Science University, Portland, Oregon 97239, USA;
- 3Department of Pathology, Oregon Health & Science University, Portland, Oregon 97239, USA;
- 4Department of Diagnostic Radiology, Oregon Health & Science University, Portland, Oregon 97239, USA;
- 5Legacy Health, Department of Cytogenetics, Portland, Oregon 97209, USA;
- 6Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine at University of Southern California, Los Angeles, California 90033, USA;
- 7Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon 97239, USA
- Corresponding author: woodmat{at}ohsu.edu; davarem{at}ohsu.edu
Abstract
Chromosomal rearrangements of the NTRK genes generate kinase fusions that are targetable oncogenic drivers in diverse adult and pediatric malignancies. Despite robust clinical response to targeted NTRK inhibition, the emergence of therapeutic resistance poses a formidable clinical challenge. Here we report the characterization of an ETV6-NTRK3 fusion–driven pediatric glioma that progressed through NTRK-targeted treatments with entrectinib and selitrectinib. Genetic analysis of multifocal recurrent/resistant lesions identified a previously uncharacterized NTRK3 p.G623A and a known p.G623E resistance mutation, in addition to other alterations of potential pathogenic impact. Functional studies using heterologous reconstitution model systems and patient-derived tumor cell lines establish that NTRK3G623A and NTRK3G623E mutated kinases exhibit reduced sensitivity to entrectinib and selitrectinib, as well as other NTRK inhibitors tested herein. In summary, this genetic analysis of multifocal recurrent/resistant glioma driven by ETV6-NTRK3 fusion captured a cross section of resistance-associated alterations that, based on in vitro analysis, likely contributed to resistance to targeted therapy and disease progression.
Footnotes
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[Supplemental material is available for this article.]
- Received May 25, 2021.
- Accepted July 26, 2021.
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