title: An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101.
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.
  
  
  CONCLUSIONS
  TRK fusions have been deemed putative oncogenic drivers, but their clinical significance remained unclear. A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions.
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado. robert.doebele@ucdenver.edu.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Doebele
authors.affiliation: Oregon Health and Science University Knight Cancer Institute, Portland, Oregon.
authors.forename: Lara E
authors.initials: LE
authors.lastname: Davis
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Aria
authors.initials: A
authors.lastname: Vaishnavi
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Anh T
authors.initials: AT
authors.lastname: Le
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Adriana
authors.initials: A
authors.lastname: Estrada-Bernal
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Stephen
authors.initials: S
authors.lastname: Keysar
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Aisner
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Deborah
authors.initials: D
authors.lastname: Morosini
authors.affiliation: Loxo Oncology, South San Francisco, California.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Tuch
authors.affiliation: Loxo Oncology, South San Francisco, California.
authors.forename: Michele
authors.initials: M
authors.lastname: Fernandes
authors.affiliation: Loxo Oncology, South San Francisco, California.
authors.forename: Nisha
authors.initials: N
authors.lastname: Nanda
authors.affiliation: Loxo Oncology, South San Francisco, California.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012509:Sarcoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D034904:Lamin Type A; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C065400:oncogene protein trk; C000609083:larotrectinib