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J Clin Invest. 2018 Aug 31;128(9):3819-3825. doi: 10.1172/JCI120787. Epub 2018 Aug 6.

Oncogenic TRK fusions are amenable to inhibition in hematologic malignancies.

Author information

1
Human Oncology and Pathogenesis Program and.
2
Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
3
Foundation Medicine Inc., Cambridge, Massachusetts, USA.
4
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
6
Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
7
Tufts University Medical Center, Boston, Massachusetts, USA.
8
Loxo Oncology Inc., South San Francisco, California, USA.
9
Developmental Therapeutics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Abstract

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition.

KEYWORDS:

Cancer; Hematology; Oncogenes; Oncology; Signal transduction

PMID:
29920189
PMCID:
PMC6118587
DOI:
10.1172/JCI120787
[Indexed for MEDLINE]
Free PMC Article

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