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      An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101.

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          Abstract

          Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancer-related downstream signaling pathways. These TRK fusions occur rarely, but in a diverse spectrum of tumor histologies. LOXO-101 is an orally administered inhibitor of the TRK kinase and is highly selective only for the TRK family of receptors. Preclinical models of LOXO-101 using TRK-fusion-bearing human-derived cancer cell lines demonstrate inhibition of the fusion oncoprotein and cellular proliferation in vitro, and tumor growth in vivo. The tumor of a 41-year-old woman with soft-tissue sarcoma metastatic to the lung was found to harbor an LMNA-NTRK1 gene fusion encoding a functional LMNA-TRKA fusion oncoprotein as determined by an in situ proximity ligation assay. In a phase I study of LOXO-101 (ClinicalTrials.gov no. NCT02122913), this patient's tumors underwent rapid and substantial tumor regression, with an accompanying improvement in pulmonary dyspnea, oxygen saturation, and plasma tumor markers.

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          Author and article information

          Journal
          Cancer Discov
          Cancer discovery
          2159-8290
          2159-8274
          Oct 2015
          : 5
          : 10
          Affiliations
          [1 ] University of Colorado Cancer Center, Aurora, Colorado. robert.doebele@ucdenver.edu.
          [2 ] Oregon Health and Science University Knight Cancer Institute, Portland, Oregon.
          [3 ] University of Colorado Cancer Center, Aurora, Colorado.
          [4 ] Foundation Medicine, Cambridge, Massachusetts.
          [5 ] Loxo Oncology, South San Francisco, California.
          Article
          2159-8290.CD-15-0443 NIHMS712801
          10.1158/2159-8290.CD-15-0443
          26216294
          69f6b1d5-cd86-4d13-a09d-9d8bb49e9dc2
          ©2015 American Association for Cancer Research.
          History

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