Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion-Positive Tumor Cells in a Brain Metastasis Model

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Akihiro NishiyamaSeiji Yano

Abstract

Purpose: Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although entrectinib is effective in the treatment of central nervous system (CNS) metastases that express NTRK1 fusion proteins, acquired resistance inevitably results in recurrence. The CNS is a sanctuary for targeted drugs; however, the mechanism by which CNS metastases become entrectinib-resistant remains elusive and must be clarified to develop better therapeutics.Experimental Design: The entrectinib-resistant cell line KM12SM-ER was developed by continuous treatment with entrectinib in the brain metastasis-mimicking model inoculated with the entrectinib-sensitive human colon cancer cell line KM12SM, which harbors the TPM3-NTRK1 gene fusion. The mechanism of entrectinib resistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame entrectinib resistance were screened from a library of 122 kinase inhibitors.Results: KM12SM-ER cells, which showed moderate resistance to entrectinib in vitro, had acquired the G667C mutation in NTRK1 The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viab...Continue Reading

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Citations

Apr 5, 2018·Cancers·Allison M Lange, Hui-Wen Lo
Jun 21, 2019·Current Topics in Medicinal Chemistry·Zhi-Gang SunYong Qian
Feb 26, 2021·Nature Communications·Hayato MizutaRyohei Katayama
Mar 2, 2021·Acta Pharmaceutica Sinica. B·Tingting JiangLiang Ouyang
Jul 27, 2021·Frontiers in Cell and Developmental Biology·Yuyin FuJinliang Yang
Dec 16, 2019·The Lancet Oncology·Alexander DrilonUNKNOWN trial investigators

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