American Association for Cancer Research
10780432ccr171623-sup-184429_3_supp_4554466_p3s792.pdf (106.5 kB)

Sup. Figure 6: TRK-A with G595R mutation caused steric hindrance to foretinib. from Foretinib Overcomes Entrectinib Resistance Associated with the NTRK1 G667C Mutation in NTRK1 Fusion–Positive Tumor Cells in a Brain Metastasis Model

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journal contribution
posted on 2023-03-31, 19:40 authored by Akihiro Nishiyama, Tadaaki Yamada, Kenji Kita, Rong Wang, Sachiko Arai, Koji Fukuda, Azusa Tanimoto, Shinji Takeuchi, Shoichiro Tange, Atsushi Tajima, Noritaka Furuya, Takayoshi Kinoshita, Seiji Yano

The coordinates of TRK-A for the docking study of foretinib and entrectinib were prepared from the X-ray structures as stated in the Materials and Methods section. The coordinate of the G595R mutant for the docking study of foretinib was prepared using the Discovery Studio (version 4.5, BIOVIA, San Diego, CA, USA). The three-dimensional conformations of compounds were generated by OMEGA (version 3.141592-, OpenEye Scientific Software, Santa Fe, NM, USA) with default settings. Docking was performed using FRED (version 3.0.1, OpenEye Scientific Software) with constraints making a hydrogen bond with Met592. The displayed docking models had the best FRED score.


Japan Agency for Medical Research and Development




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.