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 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

127 Citations (Scopus)

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 1 2015

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Sarcoma
Neoplasms
Oncogene Proteins
Cell Proliferation
Lung
ARRY-470
tropomyosin kinase
Gene Fusion
Tumor Biomarkers
Dyspnea
Ligation
Histology
Phosphotransferases
Oxygen
Cell Line
Growth

ASJC Scopus subject areas

  • Oncology

Cite this

An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. / Doebele, Robert C.; Davis, Lara; Vaishnavi, Aria; Le, Anh T.; Estrada-Bernal, Adriana; Keysar, Stephen; Jimeno, Antonio; Varella-Garcia, Marileila; Aisner, Dara L.; Li, Yali; Stephens, Philip J.; Morosini, Deborah; Tuch, Brian B.; Fernandes, Michele; Nanda, Nisha; Low, Jennifer A.

In: Cancer Discovery, Vol. 5, No. 10, 01.10.2015, p. 1049-1057.

Research output: Contribution to journalArticle

Doebele, RC, Davis, L, Vaishnavi, A, Le, AT, Estrada-Bernal, A, Keysar, S, Jimeno, A, Varella-Garcia, M, Aisner, DL, Li, Y, Stephens, PJ, Morosini, D, Tuch, BB, Fernandes, M, Nanda, N & Low, JA 2015, 'An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101', Cancer Discovery, vol. 5, no. 10, pp. 1049-1057. https://doi.org/10.1158/2159-8290.CD-15-0443
Doebele, Robert C. ; Davis, Lara ; Vaishnavi, Aria ; Le, Anh T. ; Estrada-Bernal, Adriana ; Keysar, Stephen ; Jimeno, Antonio ; Varella-Garcia, Marileila ; Aisner, Dara L. ; Li, Yali ; Stephens, Philip J. ; Morosini, Deborah ; Tuch, Brian B. ; Fernandes, Michele ; Nanda, Nisha ; Low, Jennifer A. / An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. In: Cancer Discovery. 2015 ; Vol. 5, No. 10. pp. 1049-1057.
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AU - Le, Anh T.

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