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 viability of KM12SM-ER cells bearing the NTRK1-G667C mutation in vitro Moreover,
foretinib markedly 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
foretinib may be effective in overcoming
entrectinib resistance 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
foretinib in
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.