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

Abstract

<b>Purpose:</b> Rearrangement of the neurotrophic tropomyosin receptor kinase 1 (<i>NTRK1</i>) 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 <i>NTRK1</i> 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.<b>Experimental Design:</b> 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 <i>TPM3-NTRK1</i> 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.<b>Results:</b> KM12SM-ER cells, which showed moderate resistance to entrectinib <i>in vitro</i>, had acquired the G667C mutation in <i>NTRK1</i> The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the <i>NTRK1</i>-G667C mutation <i>in vitro</i> 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.<b>Conclusions:</b> These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the <i>NTRK1</i>-G667C mutation in <i>NTRK1</i> 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 <i>NTRK1</i>-G667C mutation, including patients with brain metastases. <i>Clin Cancer Res; 24(10); 2357-69. ©2018 AACR</i>.