Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model
2018
Purpose: Rearrangement of the neurotrophic
tropomyosin receptor kinase1 ( NTRK1 ) gene, which encodes tyrosine receptor kinase A (TRK-A), occurs in various cancers, including colon cancer. Although
entrectinibis 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
entrectinibin 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
entrectinibresistance in KM12SM-ER cells was examined by next-generation sequencing. Compounds that overcame
entrectinibresistance were screened from a library of 122 kinase inhibitors. Results: KM12SM-ER cells, which showed moderate resistance to
entrectinibin vitro , had acquired the G667C mutation in NTRK1 . The kinase inhibitor
foretinibinhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the NTRK1 -G667C mutation in vitro . Moreover,
foretinibmarkedly inhibited the progression of
entrectinib-refractory KM12SM-ER–derived liver metastases and brain tumors in animal models, predominantly through inhibition of TRK-A phosphorylation. Conclusions: These results suggest that
foretinibmay be effective in overcoming
entrectinibresistance associated with the NTRK1 -G667C mutation in NTRK1 fusion–positive tumors in various organs, including the brain, and provide a rationale for clinical trials of
foretinibin cancer patients with
entrectinib-resistant tumors harboring the NTRK1 -G667C mutation, including patients with brain metastases. Clin Cancer Res; 24(10); 2357–69. ©2018 AACR .
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