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Leukemia. 2019 Sep 24. doi: 10.1038/s41375-019-0576-8. [Epub ahead of print]

Revisiting NTRKs as an emerging oncogene in hematological malignancies.

Joshi SK1,2,3, Davare MA4,5, Druker BJ6,7,8, Tognon CE9,10,11.

Author information

1
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States.
2
Department of Physiology & Pharmacology, School of Medicine, Oregon Health & Science University, Portland, OR, United States.
3
Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States.
4
Papé Pediatric Research Institute, Oregon Health & Science University, Portland, OR, United States.
5
Division of Pediatric Hematology & Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States.
6
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States. drukerb@ohsu.edu.
7
Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States. drukerb@ohsu.edu.
8
Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, United States. drukerb@ohsu.edu.
9
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States. tognon@ohsu.edu.
10
Division of Hematology & Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, United States. tognon@ohsu.edu.
11
Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, United States. tognon@ohsu.edu.

Abstract

NTRK fusions are dominant oncogenic drivers found in rare solid tumors. These fusions have also been identified in more common cancers, such as lung and colorectal carcinomas, albeit at low frequencies. Patients harboring these fusions demonstrate significant clinical response to inhibitors such as entrectinib and larotrectinib. Although current trials have focused entirely on solid tumors, there is evidence supporting the use of these drugs for patients with leukemia. To assess the broader applicability for Trk inhibitors in hematological malignancies, this review describes the current state of knowledge about alterations in the NTRK family in these disorders. We present these findings in relation to the discovery and therapeutic targeting of BCR-ABL1 in chronic myeloid leukemia. The advent of deep sequencing technologies has shown that NTRK fusions and somatic mutations are present in a variety of hematologic malignancies. Efficacy of Trk inhibitors has been demonstrated in NTRK-fusion positive human leukemia cell lines and patient-derived xenograft studies, highlighting the potential clinical utility of these inhibitors for a subset of leukemia patients.

PMID:
31551508
DOI:
10.1038/s41375-019-0576-8

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