An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101

Robert C. Doebele, Lara E. Davis, Aria Vaishnavi, Anh T. Le, Adriana Estrada-Bernal, Stephen Keysar, Antonio Jimeno, Marileila Varella-Garcia, Dara L. Aisner, Yali Li, Philip J. Stephens, Deborah Morosini, Brian B. Tuch, Michele Fernandes, Nisha Nanda, Jennifer A. Low

Research output: Contribution to journalArticle

170 Scopus citations

Abstract

Oncogenic TRK fusions induce cancer cell proliferation and engage critical cancerrelated 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. SIGNIFICANCE: 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.

Original languageEnglish (US)
Pages (from-to)1049-1057
Number of pages9
JournalCancer discovery
Volume5
Issue number10
DOIs
StatePublished - Oct 2015
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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    Doebele, R. C., Davis, L. E., Vaishnavi, A., Le, A. T., Estrada-Bernal, A., Keysar, S., Jimeno, A., Varella-Garcia, M., Aisner, D. L., Li, Y., Stephens, P. J., Morosini, D., Tuch, B. B., Fernandes, M., Nanda, N., & Low, J. A. (2015). An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer discovery, 5(10), 1049-1057. https://doi.org/10.1158/2159-8290.CD-15-0443