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

• Published in: Clinical cancer research Vol. 24; no. 10; pp. 2357 - 2369
• Main Authors: Nishiyama, Akihiro, Yamada, Tadaaki, Kita, Kenji, Wang, Rong, Arai, Sachiko, Fukuda, Koji, Tanimoto, Azusa, Takeuchi, Shinji, Tange, Shoichiro, Tajima, Atsushi, Furuya, Noritaka, Kinoshita, Takayoshi, Yano, Seiji
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.05.2018
• Subjects: Amino Acid Substitution; Anilides - chemistry; Anilides - pharmacology; Animal models; Animals; Benzamides - chemistry; Benzamides - pharmacology; Brain; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; Cancer; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Central nervous system; Clinical trials; Colon; Colon cancer; Colorectal cancer; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm - drug effects; Enzyme inhibitors; Experimental design; Gene fusion; Gene rearrangement; Heterografts; Humans; Indazoles - chemistry; Indazoles - pharmacology; Liver; Medical research; Metastases; Metastasis; Mice; Mimicry; Models, Molecular; Mutation; NTRK1 gene; Oncogene Proteins, Fusion - genetics; Organs; Patients; Phosphorylation; Proteins; Quinolines - chemistry; Quinolines - pharmacology; Receptor, trkA - chemistry; Receptor, trkA - genetics; Structure-Activity Relationship; Tropomyosin; Tumor cells; Tumors; Tyrosine; Viability
• DOI: 10.1158/1078-0432.CCR-17-1623
• ISSN: 1078-0432

Rearrangement of the neurotrophic tropomyosin receptor kinase 1 ( ) 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 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. 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 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. KM12SM-ER cells, which showed moderate resistance to entrectinib , had acquired the G667C mutation in The kinase inhibitor foretinib inhibited TRK-A phosphorylation and the viability of KM12SM-ER cells bearing the -G667C mutation 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. These results suggest that foretinib may be effective in overcoming entrectinib resistance associated with the -G667C mutation in 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 -G667C mutation, including patients with brain metastases. .