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Alexander Drilon, MD

Gregory J. Riely, MD, PhD


NTRK Gene Fusions: Therapeutic Target in NF1-Linked Peripheral Nerve Sheath Tumors?

By: Kayci Reyer
Posted: Friday, December 9, 2022

Research presented in Acta Neuropathologica suggests that detection of NTRK gene fusions may provide new opportunities for targeted treatment in neurofibromatosis type 1 (NF1)-related malignant peripheral nerve sheath tumors. Nerve sheath tumors are a common complication in aggressive NF1 disease.

“Our study for the first time describes NF1-related malignant peripheral nerve sheath tumor–harboring subclonal NTRK rearrangements, with primarily good response to TRK inhibitor treatment, which could be an (additional) therapeutic agent,” noted Laura S. Hiemcke-Jiwa, MD, PhD, of the Princess Máxima Center for Pediatric Oncology, the Netherlands, and colleagues.

The study included 21 cases of NF1-linked malignant peripheral nerve sheath tumors, of which 3 harbored an NTRK1 gene fusion. Partner genes TPM3, LMNA, and CACYBP were identified. Although TMP3 and LMNA have been previously recognized as partners for common driver fusion genes in spindle cell neoplasms associated with NTRK, the authors noted that CACYBP has not been reported as an NTRK partner in the existing literature. Of the three tumors harboring an NTRK gene fusion, two originated from plexiform neurofibroma and contained biallelic NF1 mutations, and one had clinical indicators of NF1 but did not show multiple hits. However, all three had rearrangements that appeared to be subclonal molecular events, which impacts MAPK signaling through the activation of transmembrane tyrosine kinase.

Furthermore, one of the three tumors with an NTRK gene fusion initially responded to TRK inhibitor monotherapy but was followed by disease progression. The authors cited previous findings suggesting a combination treatment targeting TRK plus MEK may increase the efficacy of targeted therapy in tumor with NTRK gene fusions when another MAPK signaling pathway alteration is activated.

Disclosure: The study authors reported no conflicts of interest.

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